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Toxoplasmosis - A Global Threat. Correlation of Latent Toxoplasmosis with Specific Disease Burden in a Set of 88 Countries

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Background Toxoplasmosis is becoming a global health hazard as it infects 30-50% of the world human population. Clinically, the life-long presence of the parasite in tissues of a majority of infected individuals is usually considered asymptomatic. However, a number of studies show that this 'asymptomatic infection' may also lead to development of other human pathologies.Aims of the studyThe purpose of the study was to collect available geoepidemiological data on seroprevalence of toxoplasmosis and search for its relationship with mortality and disability rates in different countries.Methods and findingsPrevalence data published between 1995-2008 for women in child-bearing age were collected for 88 countries (29 European). The association between prevalence of toxoplasmosis and specific disease burden estimated with age-standardized Disability Adjusted Life Year (DALY) or with mortality, was calculated using General Linear Method with Gross Domestic Product per capita (GDP), geolatitude and humidity as covariates, and also using nonparametric partial Kendall correlation test with GDP as a covariate. The prevalence of toxoplasmosis correlated with specific disease burden in particular countries explaining 23% of variability in disease burden in Europe. The analyses revealed that for example, DALY of 23 of 128 analyzed diseases and disease categories on the WHO list showed correlations (18 positive, 5 negative) with prevalence of toxoplasmosis and another 12 diseases showed positive trends (p
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Toxoplasmosis – A Global Threat. Correlation of Latent
Toxoplasmosis with Specific Disease Burden in a Set of
88 Countries
Jaroslav Flegr
1
*, Joseph Prandota
2
, Michaela Sovic
ˇkova
´
1
, Zafar H. Israili
3
1Department of Biology, Faculty of Science, Charles University in Prague, Prague, Czech Republic, 2Department of Social Pediatrics, Faculty of Health Sciences, Wroclaw
Medical University, Wroclaw, Poland, 3Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America
Abstract
Background:
Toxoplasmosis is becoming a global health hazard as it infects 30–50% of the world human population.
Clinically, the life-long presence of the parasite in tissues of a majority of infected individuals is usually considered
asymptomatic. However, a number of studies show that this ‘asymptomatic infection’ may also lead to development of
other human pathologies.
Aims of the Study:
The purpose of the study was to collect available geoepidemiological data on seroprevalence of
toxoplasmosis and search for its relationship with mortality and disability rates in different countries.
Methods and Findings:
Prevalence data published between 1995–2008 for women in child-bearing age were collected for
88 countries (29 European). The association between prevalence of toxoplasmosis and specific disease burden estimated
with age-standardized Disability Adjusted Life Year (DALY) or with mortality, was calculated using General Linear Method
with Gross Domestic Product per capita (GDP), geolatitude and humidity as covariates, and also using nonparametric partial
Kendall correlation test with GDP as a covariate. The prevalence of toxoplasmosis correlated with specific disease burden in
particular countries explaining 23% of variability in disease burden in Europe. The analyses revealed that for example, DALY
of 23 of 128 analyzed diseases and disease categories on the WHO list showed correlations (18 positive, 5 negative) with
prevalence of toxoplasmosis and another 12 diseases showed positive trends (p,0.1). For several obtained significant
correlations between the seroprevalence of toxoplasmosis and specific diseases/clinical entities, possible pathophysiolog-
ical, biochemical and molecular explanations are presented.
Conclusions:
The seroprevalence of toxoplasmosis correlated with various disease burden. Statistical associations does not
necessarily mean causality. The precautionary principle suggests however that possible role of toxoplasmosis as a triggering
factor responsible for development of several clinical entities deserves much more attention and financial support both in
everyday medical practice and future clinical research.
Citation: Flegr J, Prandota J, Sovic
ˇkova
´M, Israili ZH (2014) Toxoplasmosis – A Global Threat. Correlation of Latent Toxoplasmosis with Specific Disease Burden in a
Set of 88 Countries. PLoS ONE 9(3): e90203. doi:10.1371/journal.pone.0090203
Editor: Delmiro Fernandez-Reyes, National Institute of Medical Research, United Kingdom
Received December 25, 2013; Accepted January 22, 2014; Published March 24, 2014
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for
any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Funding: The authors’ work was supported by the Grand Agency of the Czech Republic (Grant No. P303/11/1398) and Charles University of Prague (grant UNCE
204004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: flegr@cesnet.cz
Introduction
Toxoplasmosis, a disease caused by the obligate apicomplexan
intracellular protozoan Toxoplasma gondii,isoneoftheworldsmost
common parasites infecting most genera of warm-blooded animals
(more than 30 species of birds and 300 species of mammals). It is the
most prevalent infection in humans (estimated to be 30–50% of the
world population), more than latent tuberculosis which infects about
one-third of the human population (WHO, www.who.int/entity/tb/
publications/2009/tbfactsheet_2009update_one_page.pdf, accessed
July 2013). The definitive hosts are representatives of the felid (cat)
family. Nicolle and Manceaux (1908) first observed the parasites in the
blood and tissues of a North African rodent, Ctenodactylus gondii,and
named it Toxoplasma (arclike form) gondii (after the rodent host) [1].
There are three infective stages of T. gondii: a) a rapidly dividing
invasive tachyzoite; b) a slowly dividing bradyzoite in tissue cysts,
which can persist inside human cells for protracted periods; and c) an
environmental stage, the sporozoite, protected inside an oocyst. The
oocysts, remarkably stable environmentally, are transmitted to other
hosts through inadvertent ingestion.
Seroprevalence of toxoplasmosis
Seroprevalence is a measure of the accumulated exposure
during a person’s lifetime in a particular social setting. Most of the
more than one third of the world’s human population who are
infected with T. gondii remain asymptomatic because the immune
system usually keeps the parasite from causing illness. Chronic,
usually lifelong, infection with Toxoplasma that is not accompanied
with overt clinical symptoms of toxoplasmosis disease is termed
latent toxoplasmosis while chronic infection associated with
PLOS ONE | www.plosone.org 1 March 2014 | Volume 9 | Issue 3 | e90203
continuous or recurrent clinical symptoms is termed chronic
toxoplasmosis (this form of disease is relatively rare in Europe and
Northern America). Worldwide seroprevalence of the parasite
measured by specific anti-Toxoplasma IgG antibodies varies
between 1% and 100% depending on the environmental and
socioeconomic conditions, including eating habits and health-
related practices [2–5], general level of hygiene, host susceptibility,
geographical location (geolatitude) and humidity of the soil. The
incidence of infection is higher in warmer and humid climates and
increases with age [5]. The lowest seroprevalence (,1%) was
found in some countries in the Far East and the highest (.90%) in
some parts of European and South American countries. In the
United States, the Centers for Disease Control and Prevention
(CDC) reported an overall seroprevalence of 11% [National
Health and Nutritional Examination Survey between 1999 and
2004]; another survey reported a higher number (22.5%) [6].
Nevertheless, toxoplasmosis is one of the leading causes of death
attributed to foodborne illness [7]. In European countries, the
prevalence ranges between 10% to 60%, and in some regions as
high as 90% [8]. In one study, 84% of pregnant women had serum
antibodies against the parasite [3]. Data from 88 countries are
presented in Table 1; most of the published data on seropreva-
lence are in women of childbearing age and/or those who are
pregnant.
In the majority of the human populations, the parasite
seroprevalence increases with age, and may vary by gender
[6,94]. Latitudinal variability in the geoseroprevalence of the
parasite may be due to local rainy conditions (because oocysts live
longer in humid conditions), and low altitude regions (especially at
mid-latitudes); a north-south seroprevalence gradient has also been
reported in animals [9,95,96].
The seroprevalence of toxoplasmosis is high in immunocom-
promised patients, such as those infected with human immuno-
deficiency virus (HIV), and transplant or cancer patients treated
with immunosuppressive agents [5,97,98].
It may be pointed out that the different serological methods
used to obtain prevalence data are not standardized, and vary in
sensitivity, specificity, and predictive values. As a consequence, no
two tests produce the same results in all cases, even when carried
out in the same laboratory [5].
Genotypes and virulence of T. gondii
T. gondii strains are highly diverse but only a few lineages are
widely spread. Different genotypes of the parasite show great
diversity in pathogenicity and drug sensitivity. Some atypical
strains have also been detected. In Europe, North America, and
Africa, there are three dominant clonal lineages of T. gondii called
type I (RH, GT1,CAST), type II (ME49, WIL, HART), and type
III (VEG, MOO, SOU), as well as many atypical genotypes which
differ in prevalence, virulence, migratory capacity within the host,
and ability to convert to the bradyzoite cyst phase [99–101].
Different strains of the parasite induce different cytokine responses
[102], thus triggering development of various clinical and
biochemical disturbances in the host, including modulation of
the host cell proteome [103,104]. Mice fed as few as 1 oocyst of T.
gondii serotype I and several atypical strains died of acute
toxoplasmosis within 21 days post inoculation, while some T.
gondii type II, and III strains were less virulent [105]. In North
America, the parasite serotype II and NE-II causes congenital
toxoplasmosis, while prematurity and severity of disease at birth
was associated with the coccidian NE-II serotype [106]. This
serotype was also associated with rural residence, lower socioeco-
nomic status and Hispanic ethnicity (P,0.01–0.001) [106]. A
greater variety of genotypes are found in South America and
Africa than in North America and Europe [107,108], suggesting
that in these continents sexual replication of the parasite occurs
more frequently than in any other part of the world [109]. This
genetic divergence may contribute to the higher prevalence of
seropositivity and ocular disease due to T. gondii, as exemplified by
the higher prevalence of toxoplasmosis and Toxoplasma-induced
eye disease in southern Brazil than in any other part of the world
[110].
Transmission of T. gondii
Animals are infected by eating infected animals, by ingestion of
or coming in contact with feces of an infected cat, or by
transmission from mother to fetus. In humans, cats are the
primary source of infection (contact with fecal material), but other
pets may also be the secondary source of infection [3,111,112].
The seroprevalence of toxoplasmosis in the Arctic region proves
that T. gondii can thrive in the absence of cats [113].
Contact with raw meat of infected animals, especially pork, is a
more significant source of human infections in some countries,
such as in Poland, where the majority of pigs, cattle and sheep
(approximately 80%) test positive for T. gondii [8,114]. Transmis-
sion of the parasite can also occur by drinking municipal/well
unboiled and unbottled water containing oocysts, exposure to
contaminated soil, contaminated milk, exposure of children
playing in sandpits, geophagia [115,116], eating raw or under-
cooked meat, especially venison [117] or rabbits [118], raw
oysters, clams, or mussels [119], consumption of unwashed raw
fruits and vegetables contaminated with the oocytes [117], blood
transfusion [120–122], maternal-fetal passage of blood cells
(including placental trophoblasts) [123,124], solid organ allografts
[125,126], bone marrow transplantation [127], allogeneic stem
cell transplantation [128], sputum [129], breast milk [130,131],
and semen [132] (thus, probably the infection may be transmitted
via both vaginal and oral sex, significantly more frequently from
seropositive to passive sex partner than vice-versa (P,0.001)
[133]). Poor hygiene, lower socioeconomic status and less
education, as well as exposure to certain strains of T. gondii may
also contribute to a higher rate of infection [134].
Cellular mechanism(s) of infection
T. gondii is remarkable in its ability to invade a wide variety of
host cells. Invasion is an active process relying on parasite motility
and the sequential secretion of proteins from secretory organelles,
the micronemes, rhoptries, and the dense granules. T. gondii can
invade and multiply inside any nucleated cell type including
epithelial cells and blood leukocytes [135]. A preference to infect
and multiply inside myeloid cells in vitro has also been reported
[136], and several studies in mice indicate that the dendritic cells
as well as monocytes/macrophages function as systemic parasite
transporters (‘‘Trojan horses’’) during infection [137–142]. The
parasite can be transmitted from infected dendritic cells to NK
cells [143], and thus, low levels of NK cells found in pregnant
women may suggest transmission of the parasite [144]. Differential
infectivity and division rate of intracellular tachyzoites in human
peripheral blood leukocytes and other primary human cells in vitro
has been demonstrated depending on the cell characteristics [136].
Clinical manifestations of toxoplasmosis
It is believed that the majority of immunocompetent individuals
infected with T.gondii remain asymptomatic or have a subclinical
course with minor symptoms [145]. It is nevertheless the most
common food-borne parasitic infection requiring hospital treat-
ment [146], and the third most common cause of hospitalization
due to food-borne infection [147]. Both competent and immuno-
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Table 1. Prevalence of latent toxoplasmosis in women of childbearing age in various countries.
Country Prevalence (%) Adj. Prevalence (%) Reference Period No.
Albania 49 42 [10] 2004–2005 496
Argentina 60 53 [11] 2001 1007
Australia 23 16 [12] 2001 308
Austria 42 36 [13] 1997 4601
Bahrain 22 16 [14] 2005 3499
Bangladesh 38 38 [15] 1995–1996 286
Belgium 49 42 [16] 2004 16541
Benin 54 47 [17] 1993 211
Brazil 50 50 [18] 2012 2136
Burkina Faso 25 25 [19] 2006 336
Cameroon 77 70 [20] 1992 1014
Canada 20 17 [21] 2006 NA
Colombia 54 54 [22] 2006 630
Costa Rica 76 76 [23] 1996 1234
Croatia 29 24 [24] 2000 1109
Cuba 55 55 [25] 2004 526
Czech Republic 20 16 [26] 2007 1053
Congo 60 60 [27] 1990 2897
Denmark 28 20 [28] 1999 89873
Egypt 42 36 [29] 1995 62
Estonia 68.6 45 [30] 1999–2000 1277
Ethiopia 74 66 [31] 2012 1016
Finland 20 17 [32] 1989 16733
France 54 47 [33] 1995 13459
Gabon 71 71 [34] 1997 767
Germany 63 50 [35] 1999 4854
Greece 25 21 [36] 2004 5532
Grenada 57 50 [37] 2006 534
Hungary 45 39 [38] 2000 31759
Chile 39 33 [39] 1996 7536
China 11 11 [40] 2006 235
Iceland 13 8 [30] 1998 440
India 35 35 [41] 2003 180
Indonesia 53 46 [42] 2006 17735
Iran 39 33 [43] 2007 576
Iraq 49 42 [44] 2002 254
Ireland 34 25 [45] 2008 20252
Israel 21 17 [46] 1989 213
Italy 23 16 [47] 2004 3426
Jamaica 57 57 [48] 1986 1604
Japan 10 8 [49] 2011 4466
Jordan 47 40 [50] 2005 280
Kuwait 46 53 [51] 2002–2005 225
Lebanon 62 62 [52] 2010 232
Libya 45 34 [53] 2007 143
Lithuania 40 34 [54] 1991 NA
Macedonia 22 18 [55] 2005 NA
Madagascar 84 84 [56] 1992 599
Malaysia 49 42 [57] 2003 200
Mexico 49 49 [58] 2006 NA
Correlation of Toxoplasmosis with Disease Burden
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compromised persons can develop the disease, especially retino-
choroiditis (ocular toxoplasmosis) [2,145,148]. In non-pregnant
immunocompetent adults, acute disease may also lead to impaired
eye sight [149,150]. For example, in the United States, one million
new infections occur each year, which result in approximately 20
000 cases of retinal pathology [151]. Primary infection in pregnant
women is a matter of great concern, since it can be transmitted to
the fetus leading to spontaneous abortion or stillbirth. A newborn
exposed to T. gondii in utero may develop congenital toxoplasmosis
with major ocular and neurological consequences. In immuno-
suppressed (HIV, organ transplant or cancer) patients, the
infection can lead to life-threatening cerebral toxoplasmosis
[97,98,152].
Symptomatic infection with the parasite can be categorized into
four groups: 1) cervical lymphadenopathy, headache, fever, sore
throat, and myalgia, with possibility of splenomegaly and brief
Table 1. Cont.
Country Prevalence (%) Adj. Prevalence (%) Reference Period No.
Montenegro 27 23 [55] NA NA
Morocco 51 44 [59] 2007 2456
Mozambique 19 13 [60] 2008 150
Nepal 55 55 [61] 1998 345
Netherlands 35 26 [62] 2004 7521
New Zealand 35 26 [63] 2004 500
Nigeria 78 71 [64] 1992 352
Norway 11 9 [65] 1993 35940
Pakistan 33 28 [66] 1997 105
Papua New Guinea 18 15 [67] 1990 197
Peru 39 33 [68] NA NA
Poland 40 34 [69] 2003 4916
Portugal 24 17 [70] 2011 401
Qatar 35 30 [71] 2005–2008 1857
South Korea 4 3 [72] 2000 NA
Romania 44 38 [73] 2008 184
Sao Tome and Principe 75 68 [74] 2007 499
Saudi Arabia 32 27 [75] 1991 921
Senegal 40 34 [76] 1993 353
Serbia 31 26 [55] 2007 765
Singapore 17 14 [77] NA 120
Slovakia 22 18 [78] 2008 656
Slovenia 25 21 [79] 2002 21270
Spain 32 23 [80] 2004 16362
Sudan 42 36 [81] 2003 487
Sweden 18 13 [82] 2001 40978
Switzerland 35 26 [83] 2006 NA
Tanzania 35 35 [84] 1991 549
Thailand 13 11 [83] 2001 1200
Togo 75 68 [85] 1991 620
Trinidad and Tobago 43 43 [86] 2008 450
Tunisia 43 37 [87] 1996 2231
Turkey 54 47 [88] 2005 1149
United Arab Emirates 23 19 [89] 1997 1503
UK 9 6 [90] 2005 1897
USA 11 9 [91] 2007 NA
Venezuela 38 38 [92] 2006 446
Vietnam 11 9 [93] 2003 300
The second and third column show prevalence of toxoplasmosis and prevalence adjusted to a standard age of 22 years to account for variation in childbearing age in
across countries (column 1) using the formula Prevalence
adj
=12(12Prevalence)(22/childbearing age) [9]. Column 5 shows year(s) when the study was performed and
column 6 shows number of women in the sample. For Macedonia, the 2004 WHO data were not available therefore this 30
th
European country was not included in our
data set.
doi:10.1371/journal.pone.0090203.t001
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erythematous (maculopapular) rash; 2) typhus-like exanthematous
form with myocarditis, meningoencephalitis, atypical pneumonia
and possibly death; 3) retinochoroiditis, which may be severe,
requiring enucleation; and 4) central nervous system involvement
[153]. In addition, several reports suggest that T. gondii infection
may be responsible for additional wide range of symptoms, and
development of several clinical entities (summarized in Table 2).
Some of the clinical manifestations of T. gondii infection may be
as a result of extensive interaction of the pathogen with
approximately 3000 host genes or proteins possibly because of
frequent host/pathogen antigen homology that disrupts/creates/
triggers host specific metabolic pathways, and finally contributes to
the development of endophenotypes of different diseases [154].
The parasite and concomitant viral and/or bacterial infections
scavenge important metabolites from host cells and/or donate
other compounds to the host causing unwanted effects. In
addition, T. gondii-derived autoantibodies also play an important
role in the pathology associated with the parasite [154].
Association of seroprevalence of toxoplasmosis with
other pathologies
Due to the fact that T. gondii infection is omnipresent and
associated with development of many pathologies in humans and
animals, including the disease burden of congenital toxoplasmosis,
as represented by disability-adjusted life years (DALY) being the
highest among all foodborne pathogens [149], the purpose of this
work was to collectively evaluate available geoepidemiological data
on the parasite worldwide national seroprevalence variations and
their relationship with mortality and disability rates. In the
analyses, gross domestic product (GDP) per capita as a covariate was
used because earlier it was argued and demonstrated that culture-
level correlations need to be controlled for regional socioeconomic
parameters [9,215,322]. If possible (i.e. in multivariate GLM
analyses), two potential confounding variables that could strongly
influence both the survival of Toxoplasma oocysts in soil and a
course of various diseases, namely the average latitude (proxy for
temperature) and the average relative humidity of particular
countries have also been included into the statistical models. In this
study we found many positive and some negative associations
between the prevalence of toxoplasmosis and various diseases
burdens. The number and strength of these associations were
much higher than could be expected by chance. Still, it must be
emphasized that statistical association does not mean causality.
Based on the finding of a statistical association between two
phenomena, one cannot determine which of them is the cause and
which is the effect – in other words, whether event A causes event
B, or whether event B causes event A. Not only we are unable to
determine whether event A causes B, or B causes A, but sometimes
there is an (unknown) event C that causes both A and B.
Therefore, all effects observed in the present exploratory study as
well as all suggested biological or medical interpretations must be
considered just as potential stimuli for the next, more focused
research (search for unknown confounders and for independent
evidence) that must follow.
Methods
Mortality and Burden of Diseases data
The data on disease burden, mortality and Disability Adjusted
Life Year (DALY), were obtained from the table ‘‘Mortality and
Burden of Diseases Estimates for WHO Member States in 2004’’
published by WHO [323] and available at: www.who.int/
evidence/bod. The publication can be downloaded from the
website: http://www.who.int/healthinfo/global_burden_disease/
2004_report_update/en/index.html; accessed July 2013). Sum-
mary tables present the best estimates of WHO – based on the
evidence available in mid-2008 – rather than from the official
estimates of Member States. Methods and data sources are
summarized in the Annexes of the ‘‘Global burden of disease:
2004 update’’ [323], and the methodology used is described in
more details elsewhere [324]; also available at: http://www.dcp2.
org/pubs/GBD; accessed July 2013.
The Disability Adjusted Life Year (DALY) has been defined
[323] as ‘‘a health gap measure that extends the concept of
potential years of life lost due to premature death and also to
include equivalent years of ‘healthy’ life lost by virtue of being in a
state of poor health or disability.’’ Thus, the DALY combines in
one measure the time lived with disability and the time lost due to
premature mortality. One DALY can be thought of as one lost
year of ‘healthy’ life, while the ‘burden of disease’ as a measure of
the gap between current health status and an ideal situation where
everyone lives into old age free of disease and disability. The
method of calculation of age-standardized DALY has been
described earlier [323].
Data collection for prevalence of toxoplasmosis
In the literature, most of toxoplasmosis prevalence (seroprevalence)
data are available only for women in childbearing age. Therefore, all
available data collected for this population were published mostly
between 1995–2008; the final database was obtained from 88
countries (29 European). When more than one estimation of
prevalence of toxoplasmosis was available for a particular country,
we gave priority to multicenter studies performed between 1998–
2004. When the studies published different prevalence data for
various regions or different years we calculated an unweighted
arithmetic mean. The obtained data were adjusted to a standard age
22 years to eliminate differences in prevalence caused by different
childbearing ages in various countries [325] were kindly provided by
Mudhakar Dama) using the formula:
Prevalenceadj ~1{1{PrevalenceðÞ
(22=child bearing age) 9½:
Statistical Methods
All statistical tests except partial Kendall correlation test were
performed independently with SPSS 21 and Statistica 10.0. The
association between seroprevalence of toxoplasmosis and specific
disease burden estimated with age standardized DALY was
calculated using nonparametric partial Kendall correlation test
[326,327] with Gross Domestic Product per capita (GDP) as
covariate. Because the results of similar analyses performed with
the General Linear Model (GLM) method were qualitatively the
same, GLM data were primarily interpreted in the Discussion
section of present study. The GLM is more sensitive for the quality
of data (e.g. to presence of outliers and non-Gaussian distribution
of data, etc.), however, it enables to control for more than one
covariate. In the present analysis, we controlled for GDP,
geographical latitude and annual mean of relative humidity of
particular countries using data available at http://data.worldbank.
org/indicator/NY.GDP.PCAP.CD (accessed 10.12. 2013) and
http://www.climatemps.com/ (accessed 2.4. 2013). No formal
corrections for multiple tests were carried out, however, the
fraction of significant results largely exceeded a theoretical value of
5 false positive results per 100 tests.
The medical importance of the association was expressed as
regression coefficient ‘B’, the slope of the regression line. The
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Table 2. Diseases and clinical entities associated with T. gondii infection.
Disease/Clinical entity References
Congenital toxoplasmosis (encephalitis; chorioretinitis; neonatal mortality) [100,149,155–158]
Psychosis; schizophrenia; bipolar disorder [159–166]
Mood disorders; suicide; depression (?) [167–174]
Obsessive-compulsive disorder [175,176]
Attention/concentration deficit hyperactivity disorder [175,177]
Anorexia [178–181]
Autism spectrum disorders [164,177,182–185]
Down’s syndrome [182,186–188]
Alzheimer’s disease [182,189–191]
Parkinson’s disease [192,193]
Migraine; other headaches [194–197]
Idiopathic intracranial hypertension [177,180,198]
Pseudotumor cerebri [180,198]
Aseptic meningitis [180,198]
Mollaret meningitis [199]
Epilepsy [200,201]
Aphasia and epilepsy (Landau-Kleffner syndrome) [202]
Facial nerve palsy (Bell’s palsy) [203]
Hearing loss [204,205]
Central diabetes insipidus; syndrome of inappropriate antidiuretic hormone secretion [156,206–209]
Hypothalamo-pituitary dysfunction; panhypopituitarism [209–211]
Brain tumors (meningioma; ependymoma; glioma) [196,212–216]
Non-Hodgkin’s lymphoma [217,218]
Neoplasia [216,219–221]
Melanoma [216,222–226]
Breast cancer [227]
Carcinoma of female genitalia, including cervical tissue [228]
Chronic heart failure; myocarditis; arrhythmia [229–231]
Inflammatory bowel disease [232–234]
Ulcerative colitis [232]
Crohn’s disease [232]
Celiac disease [232,235]
Abdominal hernia [233,236]
Hepatitis, including HCV infection [237–246]
Granulomatous liver disease [247,248]
Liver cirrhosis; granulomatous liver disease; impaired liver function [242–244,249–253]
Primary biliary cirrhosis; biliary atresia; cholestatic disorders [254–261]
Diabetes mellitus type 1 and 2 [189,262–264]
Goitre; iodine deficiency [265–268]
Hashimoto’s thyroiditis [269]
Graves’ disease; thyroid adenoma [269–271]
Rheumatoid arthritis; Still’s disease [272–277]
Polymyositis [231,278–283]
Systemic sclerosis [277,284,285]
Systemic lupus erythematosus [286]
Wegener’s granulomatosis; other vasculitides 205; 215 [277,287]
Anti-phospholipid syndrome [287]
Cryoglobulinemia [287]
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higher is the absolute value of B the greater is the positive or
negative impact of the predictor variable (here prevalence of
toxoplasmosis) on the dependent variable (here DALY or
mortality). The strength of statistical association is expressed as
Eta
2
, which reflects the proportion of variance in the dependent
variable (the DALY or mortality) associated with or accounted for
by each of the main effects, interactions, and error in an ANOVA
study (the prevalence of latent toxoplasmosis) [328] pp. 54–55,
[329] pp. 317–319. The statistically significant results, i.e. the
associations with p value ,0.05 and trends, i.e. the associations
with p value ,0.1 (significant in one-sided but not in two-sided
tests) were listed in the tables and in the main text.
Results and Discussion
Correlation of toxoplasmosis prevalence with GDP per
capita, geolatitude and humidity
Fig. 1 suggests that the prevalence of toxoplasmosis correlates
with GDP, and possibly also with latitude and humidity for the
countries for which the information on toxoplasmosis prevalence is
reported. For the whole set of countries (n = 88), the prevalence of
toxoplasmosis correlated positively with GDP per capita (Spear-
man R = 20.484, p,0.001) and latitude (Spearman R = 20.449,
p,0.001), and non-significantly positively correlated with the
humidity (Spearman R = 0.180, p = 0.093) in the univariate
nonparametric Spearman test. For European countries (n = 29)
all three correlations were not significant (p.0.151) and for non-
European countries (n = 59) the prevalence of toxoplasmosis
correlated negatively with GDP per capita (Spearman R = 2
0.382, p = 0.003) and latitude (Spearman R = 20.396, p,0.002),
and positively with humidity (Spearman R = 0.308, p = 0.017).
The multivariate GLM analyses with GDP, latitude and humidity
as independent variables showed negative correlation with GDP
(all countries: p = 0.006, Eta
2
= 0.085; European: p = 0.044,
Eta
2
= 0.153; non-European: p = 0.022, Eta
2
= 0.092). For the
latitude and humidity, the results differed between European and
non-European countries (latitude all countries: p = 0.014,
Eta
2
= 0.070; European: p = 0.055, Eta
2
= 0.135; non-European:
p = 0.073, Eta
2
= 0.057; humidity all countries: p = 0.056,
Eta
2
= 0.043; European: p = 0.037, Eta
2
= 0.162; non-European:
p = 0.356, Eta
2
= 0.016). These results suggest that the GDP, and
possibly also the latitude and humidity, should be incorporated
into the statistical models as covariates.
Correlation of toxoplasmosis prevalence with age-
standardized DALY for diseases
The present study showed that prevalence of toxoplasmosis
correlated with specific disease burden measured with age-
standardized DALY or with specific mortality in particular
countries (Fig. 2).
Because distribution of DALY and mortality for many diseases
was not normal, the analysis of association of toxoplasmosis
prevalence with disease burden was performed with two methods,
nonparametric partial Kendall correlation test and GLM analysis.
Since, a nonparametric partial Kendall correlation test enables
to control for one confounding variable, we controlled for the
GDP per capita because this variable is known to be strongly
correlated with the quality of health care and therefore with the
burden associated with many diseases. The partial Kendall
correlation test demonstrated that age standardized DALY of 57
of 128 diseases and disease categories on the WHO list showed
significant correlation (53 positive and 4 negative) with prevalence
of toxoplasmosis in all (n = 88) countries after the effect of GDP
was controlled, and further 8 diseases showed such trends (p,0.1)
(6 positive and 2), see Fig. 3. Similar analyses for 29 European
countries showed 12 significant correlations (11 positive and 1
negative) and 11 trends (10 positive and 1 negative), and for 59
non-European countries test revealed 33 significant correlations
(29 positive and 4 negative) and 10 trends (all positive), Fig 3.
GLM analyses with GDP, latitude and humidity as covariates
showed that age standardized DALY of 23 of 128 diseases and
disease categories on the WHO list had significant correlation (18
positive and 5 negative) with prevalence of toxoplasmosis in all
(n = 88) countries after the effect of GDP was controlled, and
further 12 diseases showed such trends (p,0.1) (all positive),
Similar analyses for 29 European countries showed 32 significant
correlations (29 positive and 3 negative) and 18 trends (16 positive
and 2 negative), and for 59 non-European countries had 18
significant correlations (13 positive and 5 negative) and 13 trends
(9 positive and 4 negative), Fig 4.
Table 2. Cont.
Disease/Clinical entity References
Ocular toxoplasmosis (retinochorioiditis; uveitis; blurred vision; floaters; macular scars; nystagmus;
strabismus; reduced visual acuity; blindness; scleritis; papillitis; retinal necrosis; vasculitis; retinal
detachment; vitritis; congenital cataract; neuroretinitis; atrophic optic papilla; retinitis pigmentosa)
[225,288–291]
Glaucoma [292,293]
Ovarian dysfunction [294–296]
Uterine atrophy [297]
Impaired reproductive function (T. gondii was present in testicles, epididymis, seminal vesicles,
prostate gland in rams, and caused abnormalities in sperm motility, viability and concentration
rates, weight of epididymis in rats, orchitis)
[255,296,298–300]
Nephrotic syndrome; lipoid nephrosis [250,251,255,301–306]
Scho
¨nlein-Henoch purpura [196,307,308]
Glomerulonephritis (various forms; including these with development of fibrosis); impaired kidney function [250,251,301,305,306,309–312]
Atherosclerosis; obesity; cardiovascular deaths; all-cause mortality [253,313–318]
Diverse abnormalities in aggregate personality; including aggressive behavior in animals and humans [9,319–321]
doi:10.1371/journal.pone.0090203.t002
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Correlation of toxoplasmosis prevalence with disease
mortality
Partial Kendal correlation tests also showed that mortalities
from 31 of 111 diseases and disease (WHO) categories with
nonzero mortality had significant correlation (29 positive and 2
negative) with prevalence of toxoplasmosis in 88 countries after the
effect of GNP was controlled, and further 6 diseases showed such
trends (p,0.1) (5 positive and 2 negative), see Fig. 3. Similar
analyses performed for 29 European countries demonstrated 6
significant correlations (all positive), and 11 trends (all positive)
(here only 90 diseases had the mortality data necessary for
analysis), and for 59 non-European countries showed 16 significant
correlations (14 positive and 2 negative) and 8 trends (7 positive
and 1 negative) (109 diseases had enough data for the analysis)
(Fig. 3).
GLM analyses also showed that mortalities of 12 out of 111
diseases and disease categories (for 17 diseases the mortality data
were available for less than 3 countries) revealed significant
correlation (11 positive and 1 negative) with prevalence of
toxoplasmosis in 88 countries after the effects of GDP, latitude
humidity were controlled, and further 11 diseases showed such
trends (10 positive and 1 negative), see Fig. 4. Similar analyses
performed for 29 European countries showed 11 significant
correlations (all positive) and 13 trends (all positive), and for 59
non-European countries had 11 significant correlations (8 positive
and 3 negative) and 8 trends (7 positive and 1 negative), Fig. 4.
Several explanations may be put forward for positive correlation
between prevalence of latent toxoplasmosis and the DALY or the
morbidity from a particular disease: a) T. gondii infection may
increase the risk of development of some diseases, b) certain
diseases may increase the risk of acquiring toxoplasmosis, or c)
some unknown factor(s) may increase both the risk of triggering
certain diseases and Toxoplasma infection. Similarly, there are
several possible explanations for the observed negative correla-
tions: a) infection with the parasite can increase resistance/
tolerance of the infected host to a certain disease by modulating its
innate and/or acquired cellular/humoral immunity. For example,
suppression of cellular immunity observed in in vivo as well as in
vitro systems can make the host more sensitive to infection by
certain pathogens, and at the same time protect it against
development of some autoimmune diseases. On the other hand,
chronic inflammation loci in tissues/organs can be responsible for
inducing health problems, including development of certain
tumors [214,215], and at the same time activation of the host
immune system can make local tissue environment unfavorable for
growing, proliferation and persistence of certain infectious agents.
For example, toxoplasmosis increases dopamine levels in the brain
tissue, which can protect the host against symptoms of certain
diseases, e.g. Parkinson’s disease, and at the same time it can
increase the risk for development of other pathologies, such as
schizophrenia [330,331].
In the present GLM analyses, three potential confounding
factors, the GDP per capita (which strongly correlates with quality of
health services and hygienic standards), the geolatitude (which
strongly correlates with temperature and quantity and quality of
sunlight) and humidity which influences survival of Toxoplasma
oocysts in soil), were controlled. However, many other factors,
such as cultural habits, can also influence the risk of Toxoplasma
infection, and/or other infections as well. It has been, for example,
suggested that toxoplasmosis could be a sexually transmitted
Figure 1. Correlation between prevalence of toxoplasmosis humidity, geolatitude and GDP per capita in all 88 countries. The GDP
(1000 $), latitude (u) and relative humidity (%) data are shown only for the region or locality for which latent toxoplasmosis prevalence information
(%) is reported.
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disease (STD) transferred from men to women with semen/
ejaculate [331,332]. This could explain the observed positive
correlation between the prevalence of latent toxoplasmosis and
DALY for several STDs. Finally, it is to be noted that the
incidence of a certain disease can be decreased by an increased risk
of death due to another concomitant disease.
In the next part of discussion, comments are made on the results
obtained for particular diseases, mainly the results of GLM tests as
the partial Kendall correlation tests can control for one
confounding variable only and the regression coefficient (B-value)
has more straightforward interpretation than Kendall Tau. We
have concentrated on the age-standardized DALY data because
only a subset of disease could result in the death of patients under
normal conditions. The strength of correlation is usually estimated
by Eta
2
, which reflects fraction of variability of dependent variable
that can be explained by an independent variable (here, by the
prevalence of toxoplasmosis). The clinical relevance of a particular
association is however better reflected by the regression coefficient
B, which shows an increase of a dependent variable (here, the age
standardized DALY expressed in years of life lost due to
premature death per 100 000 inhabitants) that corresponds to
the increase of an independent variable per one unit (here, the
increase of prevalence of toxoplasmosis by 1%). Therefore, the B-
value reflects not only the strength of the correlation but also the
incidence of particular disease.
Association of seroprevalence of toxoplasmosis with
specific diseases in all 88 countries
All disease burden. Prevalence of toxoplasmosis explained
about 23% of between-countries variability in mortality and age-
standardized DALY in Europe (mortality: B = 3.538, Eta
2
= 0.229,
p = 0.024; DALY: B = 68.18, Eta
2
= 0.227, p = 0.014). This
association was not significant for non-European countries
(mortality: B = 3.37, Eta
2
= 0.026, p = 0.239; DALY: B = 92.49,
Eta
2
= 0.030, p = 0.204) or for all 88 countries (mortality: B = 3.78,
Eta
2
= 0.031, p = 0.104; DALY: B = 98.287, Eta
2
= 0.034,
p = 0.093). Both communicable and noncommunicable diseases
were responsible for the observed association in Europe, however,
for communicative infection was significant only for DALY
(mortality: B = 0.024, Eta
2
= 0.007, p = 0.878; DALY: B = 11.44,
Eta
2
= 0.166, p = 0.039).
Noncommunicable diseases. The highest regression coef-
ficient (B = 26.33, p = 0.019) was found for the entire category of
noncommunicable diseases. In this case, a difference of 1% in the
prevalence of toxoplasmosis corresponded to a difference of 26.33
Figure 2. Correlation of prevalence of toxoplasmosis with various disease-attributed DALY for 88 WHO-member countries. The x-
axes show prevalence of toxoplasmosis (%) in women of childbearing age and y-axes the number years of ‘healthy’ life lost by virtue of being in a
state of poor health or disability due to particular disease per 100,000 inhabitants in 2004.
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DALY per 100,000 inhabitants. The prevalence of toxoplasmosis
explained 6.4% of between countries variability in DALY.
Cardiovascular diseases. The second highest regression
coefficient (B = 12.49, p = 0.026, Eta
2
= 0.058) was observed for
cardiovascular diseases. However, prevalence of toxoplasmosis
explained about 15% of variability in mortality attributed to
cardiovascular diseases in European countries subset (B = 18.23,
p = 0.048, Eta
2
= 0.153). Also, in the European countries, the
difference in prevalence of toxoplasmosis explained about 17% of
variability of ischemic heart disease (B = 8.59, p = 0.039,
Eta
2
= 0.166). Stronger correlations between prevalence of toxo-
plasmosis and heart disease, especially inflammatory heart disease,
were revealed with nonparametric partial Kendall test (comparing
the data in tables shown in Fig. 3 and 4). One may suggest that the
non-Gaussian distributions of dependent variables, e.g. a bimodal
distribution for cerebrovascular and cardiovascular disease and
highly skewed distribution for hypertensive, rheumatic and
inflammatory heart diseases (results not shown), were responsible
for the false negative results of the GLM tests.
Theoretically, the inability to control for more than one
confounding variable (here, the latitude and annual precipitation)
in the distribution-robust nonparametric tests could be responsible
for the false positive results of the partial Kendall test. However,
the present data do not support this explanation. Fig. 1 shows that
the latitude correlates negatively and the humidity positively with
the prevalence of toxoplasmosis. The Kendall correlation test
showed, for example, the positive association between hyperten-
sive heart disease and prevalence of toxoplasmosis (DALY:
p = 0.06; mortality: p = 0.008), while GLM demonstrated lack of
such association (DALY: p = 0.345; mortality: p = 0.282). The
negative association between prevalence of toxoplasmosis and
latitude (see above) could explain the positive correlation between
the disease burden for hypertensive heart disease and prevalence
of toxoplasmosis, because the disease burden for hypertensive
heart disease correlated negatively with the latitude (DALY: B = 2
3.846, Eta
2
= 0.139, p,0.001), but also negatively with humidity
(B = 22.145, Eta
2
= 0.059, p = 0.024), which is in contradiction to
the explanation). However, the negative correlation between
prevalence of toxoplasmosis and latitude could not explain the
positive correlation between prevalence of toxoplasmosis and the
inflammatory heart disease (DALY: p = 0.012, mortality:
p = 0.006), because inflammatory heart disease correlated posi-
tively with latitude (B = 0.749, Eta
2
= 0.010, p = 0.362), and
negatively with humidity (B = 21.392, Eta
2
= 0.041, p = 0.060).
This contradicts the notion that the correlations with the latitude
or humidity could be responsible for the association between
toxoplasmosis and cardiovascular diseases detected with the partial
Kendall correlation tests.
Perinatal conditions. The third highest regression coeffi-
cient (B = 9.66) was demonstrated for this category, but, it
explained only 3.3% of the variability making the correlation
non-significant (p = 0.097). The important components of this
category were prematurity and low birth weight (B = 3.43;
Eta
2
= 0.053; p = 0.034). Published data suggest that early
development of embryos in mothers with latent toxoplasmosis
was slower, although, the birth weight of newborns was
approximately the same as those of infection-free mothers [26].
These studies were performed in Czech Republic, a developed
European country, with low frequency of virulent T. gondii strains.
It is possible that the effect of toxoplasmosis on development of
embryos is qualitatively different in other parts of the world. It is
indicative that the association between prevalence of toxoplasmo-
sis and DALY for prematurity and low birth weight is much
weaker for the European countries (B = 0.320; Eta
2
= 0.004;
p = 0.761) than for others. Once again, the correlation of DALY
for perinatal conditions with prevalence of toxoplasmosis detected
with nonparametric tests were stronger than those detected with
GLM. Here, however, the correlation observed in Kendall test (in
which the GDP but not the latitude and humidity was controlled)
can be explained by correlation of both prevalence of toxoplas-
mosis and the DALY for perinatal conditions, controlling for the
latitude, because the latter correlation is negative and relatively
strong (and significant).
Congenital abnormalities. The regression coefficient was
only medium (B = 2.613; Eta
2
= 0.133; p,0.001). The correlation
was significant for the 88 countries, however, it was non-significant
for the European countries (B = 1.970; Eta
2
= 0.137; p = 0.062).
Interestingly, more than 55 years ago, it was observed that
children with Down syndrome had a much higher probability of
having mothers with latent toxoplasmosis (84%) than normal
children (32%) [333]; the probability of having fathers with latent
toxoplasmosis did not differ between children with and without
this disorder. Recently, it has been suggested that Down syndrome
may be caused by congenital T. gondii infection [182], Table 2.
This hypothesis is supported by the finding that T. gondii has a
specific protein transporter exposed at the parasite surface, with
high affinity for folic acid, which is responsible for the acquisition
and salvaging of exogenous folate compounds [187], thus leading
to folate deficiency in the host. The transport of folic acid across
the parasite plasma membrane was found to be rapid, biphasic,
bidirectional, specific, and concentration- and temperature-
dependent, and methotrexate, an antifolate, was found to be
internalized by the protozoan pathogen to the mitochondrion
[187]. In addition, it has been demonstrated that simultaneous
dietary restriction of folic acid and infection with T. gondii induces
DNA damage in peripheral blood cells of infected mice [186].
Furthermore, T. gondii infection was also associated with
nutritional deficiencies of iron and iodine [266,334,335], which
may lead to have adverse effect on the growth and development of
the fetus.
Principally different explanation of the observed association
suggest results of three studies on the influence of toxoplasmosis on
secondary sex ratio and on the rate of prenatal and early postnatal
development of children of infected mothers, These results
indicate that latent toxoplasmosis could protect the embryos with
less serious developmental disturbances against spontaneous
abortion [26,336–338]. It is possible that such beneficial activity
of the parasite could translate into positive correlation between
prevalence of toxoplasmosis and incidence and severity of
congenital abnormalities.
Lymphatic filariasis. The regression coefficient was medi-
um (B = 4.534; Eta
2
= 0.140, p = 0.072). This disease occurs in 27
countries of our data set and therefore the highly non-Gaussian
distribution of DALY (and mortalities) makes the results of GLM
analysis not fully credible. The nonparametric test showed no
significant association between filariasis and toxoplasmosis. How-
Figure 3. Correlation of mortality and Disability Adjusted Life Year (DALY) with prevalence of toxoplasmosis for all 88 WHO
member countries (29 European and 59 non-European countries). The correlations were estimated with partial Kendall correlation test with
GDP per capita as covariate. Positive Kendall Taus (red) correspond to positive and negative Taus (blue) to negative correlations. Significant results
(p,0.05) are labeled with yellow and trends (p,0.10) with green colors.
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ever, possible relationship between toxoplasmosis and filariasis
could theoretically be explained by the fact that T. gondii usually
disseminates via lymphatic system in the infected patients, who
usually have symptomatic lymphadenopathy. In addition, possible
interactions exist between toxoplasmosis-associated changes in the
host lymphatic system and a progressive clinical picture of
lymphatic filariasis (Table 2). Filariasis may therefore represent
another co-morbidity of the host infected with T. gondii.
Measles. The regression coefficient was medium (B = 4.124;
Eta
2
= 0.070; p = 0.137), and the correlation was not significant. A
possible association, if it really exists, is difficult to rationalize,
however, latent cerebral toxoplasmosis could influence suscepti-
bility to measles because of changes in the immune status of the
children (Table 2) [339,340] caused by the parasite or measles-
mumps-rubella (MMR) vaccination.
Asthma. The regression coefficient B was 1.290
(Eta
2
= 0.071, p = 0.014). An opposite direction association was
observed for European (B = 21.571, Eta
2
= 0.096, p = 0.124) and
non-European (B = 1.879, Eta
2
= 0.158, p = 0.002) countries. We
have no explanation for the positive association, but, the negative
association between T. gondii infection and asthma could be, at
least partially, explained by the anti-inflammatory effect of
histamine produced in excess in asthmatic patients, since, asthma
is a chronic inflammatory disorder associated with an increased
number of T
H
2 (T helper type 2) cells producing anti-inflamma-
tory cytokines and decreased number of T
H
1 (T helper type 1)
cells generating pro-inflammatory cytokines. Histamine modulates
the cytokine T
H
1/T
H
2 balance because it enhances secretion of
T
H
2 cytokines, such as IL-4, IL-5, IL-10, and IL-13, and inhibits
production of T
H
1 interleukins (IL-2, IFN-c, and monokine IL-12)
[341], thus exerting beneficial anti-inflammatory effects.
Epilepsy. Epilepsy had a small regression coefficient
(B = 0.972; Eta
2
= 0.112, p = 0.001), but the correlation was highly
significant. This association was observed both in European
(B = 0.816, Eta
2
= 0.193, p = 0.025) and non-European countries
(B = 0.967, Eta
2
= 0.125, p = 0.007). The association between
latent toxoplasmosis and cryptic epilepsy has already been
suggested to exist on the basis of the case control studies – for
example, see Ref. [342,343] Table 2.
Leukemia. Surprisingly, there was a strong association
between toxoplasmosis and DALY for leukemia in European
countries (B = 0.445, Eta
2
= 0.216, p = 0.017) explaining about
22% of variability in DALY. In a small study performed in 15
patients with leukemia, 10 (66.7%) individuals had increased
serum IgG, and 2 also had increased IgM antibodies to T. gondii
[219]. It is known that tachyzoites of T. gondii use a ‘‘Trojan horse’’
strategy to penetrate various tissues and organs of the infected
host. They even transform the phenotype of infected white cells
by, for example, increasing migratory activity of the infected
dendritic cells [344] and by inhibiting apoptotic activity of the
infected cells [345–349]. It is also possible that the increased risk of
various forms of cancer, including leukemia, could be as a result of
infection with T. gondii, which may cause a nonspecific chronic
local inflammation.
Cancer of the mouth/oropharynx. The regression coeffi-
cient was small (B = 1.014; Eta
2
= 0.132, p = 0.067) and the
correlation was non-significant (positive for European but negative
for non-European countries). A typical symptom of acute
toxoplasmosis is tonsillitis. Thus, it is possible that tonsillitis
leading to the development of local chronic inflammation may
result in inducing precancerous changes in predisposed individu-
als. Association of prevalence of toxoplasmosis with cancer of the
larynx in men and women, and lung cancer in men (but not with
cancer of oropharynx), has been reported [214]. In addition, one
cannot exclude that frequent oral sex could, at least in part, affect
this correlation, since, the parasite has been found in the semen
and ejaculate of both animals and humans infected with T. gondii
[331,332], see also Table 2.
Prostate cancer. Prostate cancer had a B of 0.667
(Eta
2
= 0.093, p = 0.005). An association in opposite direction
was observed for European (B = 20.235, Eta
2
= 0.091, p = 0.133)
and non-European (B = 0.820, Eta
2
= 0.130, p = 0.006) countries.
Benign prostate hypertrophy had a B of 0.214, (Eta
2
= 0.482,
p = 0.045) and this association was positive but non-significant for
non-European countries (B = 0.062, Eta
2
= 0.079, p = 0.165) and
positive and significant (B = 0.284, Eta
2
= 0.098, p = 0.018) for
European countries. It is possible that the increased incidence of
prostate cancer and hypertrophy could be related to the increased
concentration of testosterone as observed in Toxoplasma-infected
male rats [350] and men [351,352]. Histopathologic studies of the
reproductive system in male sheep experimentally infected with
the parasite showed inflammatory process in the prostate gland
and seminal vesicles strongly suggestive of Toxoplasma infection
[300] (Table 2). Thus, persistent chronic inflammation caused by
the parasite also must be taken into account in the development of
prostate cancer, although perhaps having different clinical courses
in European versus non-European countries.
Obsessive compulsive disorder. Obsessive compulsive
disorder (OCD) had a B value of 0.836, but the prevalence of
toxoplasmosis explained 28.7% of total variability in DALY (p,
0.001). For European countries the association was weaker
(B = 0.681, Eta
2
= 0.212, p = 0.018), but for non-European coun-
tries, it was nearly two times higher (B = 0.925, Eta
2
= 0.358, p,
0.001). The association between latent toxoplasmosis and OCD
has already been suggested to exist on the basis of results of a case-
control study [176], in which the authors found 47.6% seroprev-
alence of toxoplasmosis among OCD patients (n = 42) and only
19% prevalence in controls (n = 100). Both neurotransmitters,
dopamine and serotonin, are expected to play an important role in
OCD. It is possible that either an increased concentration of
dopamine, synthesized by two enzymes encoded in T. gondii
genome, and a decreased level of serotonin, the metabolite of
tryptophan degradation – the part of the host defense against
parasitic infection – could be important etiologic factors in the
development of OCD. Incidentally, OCD is not an uncommon
disease (incidence of about 3%) and is probably associated with an
increased risk of suicide [353–356]. It can be speculated that an
association between toxoplasmosis and OCD could, in part, be
responsible for the increased risk of suicides reported in
Toxoplasma-infected individuals. It is possible that the nearly twice
stronger relationship between toxoplasmosis and OCD in Euro-
pean (Eta
2
= 0.202) than in non-European (Eta
2
= 0.360) countries
could somehow be related with the negative, not positive,
relationship between the prevalence of toxoplasmosis and
incidence of suicides in non-European countries observed in our
study, see below.
Figure 4. Correlation of mortality and Disability Adjusted Life Year (DALY) with prevalence of toxoplasmosis for all 88 WHO
member countries (29 European and 59 non-European countries). The correlations were estimated with General Linear Model with GDP per
capita, latitude humidity, as covariates. Positive B (red) correspond to positive, and negative B (blue) to negative correlations. Significant results
(p,0.05) are labeled with yellow and trends (p,0.10) with green colors.
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Endocrine disorders. A regression coefficient (B) of 2.118
was observed for the category of ‘endocrine disorders’. The
prevalence of toxoplasmosis explained about 5.8% of total
variability (p = 0.028) and non-significant trends were observed
for both European and non-European countries. The positive and
negative associations between toxoplasmosis and testosterone
concentration were observed for men and women, respectively.
However, our unpublished data suggest that toxoplasmosis could
also play a role in the production of thyroid hormones. This
finding is supported by recent literature data demonstrating the
prevalence of anti-Toxoplasma IgG antibodies in patients with
thyroid autoimmunity [277,357] as well as in many other
autoimmune diseases, as compared with controls (Table 2). The
autoantibody burden has also been demonstrated even in non-
autoimmune individuals during infections [358]. Patients with
autoimmune diseases frequently present neurologic manifestations
[359], and this may further support the significant prevalence of
toxoplasmosis in patients with endocrine disorders, because central
nervous system is the most immunoprivileged organ for T. gondii
dissemination and settlement in the host. Fetal [360] and maternal
microchimerism, acting as a ‘‘Trojan horse’’ in dissemination of
the parasite, could play an important role in endocrine and other
health disorders [361].
Sexually transmitted diseases (STDs). A regression coef-
ficient (B) of 1.63 was observed for the general category of ‘sexually
transmitted diseases except AIDS’. Prevalence of toxoplasmosis
explained 4.1% of variability (p = 0.063). The association was
stronger in European countries (B = 0.413, Eta
2
= 0.215,
p = 0.017) than in non-European countries (B = 1.699,
Eta
2
= 0.041, p = 0.133). Similar effects were observed for gonor-
rhea (B = 0.175, Eta
2
= 0.213, p = 0.018) and chlamydia
(B = 0.229, Eta
2
= 0.209, p = 0.019) in Europe, but were different
for non-European countries for gonorrhoea (B = 0.549,
Eta
2
= 0.069, p = 0.049) and chlamydia (B = 0.287, Eta
2
= 0.050,
p = 0.097). We believe that the correlation of both prevalence of
toxoplasmosis and STD with other factor(s), such as a risky sexual
behavior (promiscuity and frequent unprotected sex) is responsible
for the observed positive association between prevalence of
toxoplasmosis and age/controlled DALY for STDs. It has been
suggested by other investigators [332] that Toxoplasma is frequently
transmitted by ejaculate in several animal species. An indirect
evidence exists that the same could also occur in humans [331].
Practicing oral sex or even kissing may also be another important
route of wide dissemination of the parasite among sexual partners,
in addition to intercourse.
Pertussis. Pertussis had a regression coefficient (B) of 1.81.
Prevalence of toxoplasmosis explained 10% of variability in DALY
(p = 0.003). This correlation could, at least in part, be rationalized
by the findings that in some instances immunization could shorten
the incubation period of certain diseases or convert a latent
infection/inflammation into clinically active disease. The neces-
sary precondition for such an occurrence is the presence of latent
infection or asymptomatic bacterial/viral/parasitic colonization
[362].
It has been reported that some infants and young children
develop various urinary tract diseases, such as acute renal failure,
nephrotic syndrome, or pyelonephritis, after the injection of the
whole-cell DTP vaccine [363]. Administration of DTP vaccine
caused dose-, and time-dependent biological changes in animals,
including increased hepatic mRNA expression for several cyto-
kines, marked inhibition of liver CYP450 enzymes activity,
induction of IFN-c, and enhanced NOS mRNA expression
[364,365]. In addition, a significant increase in toxoplasma-cysts
was observed in brain tissues of mice exposed to both T. gondii
infection and methylmercury (thimerosal, a vaccine preservative)
versus the parasite alone [366]. Thus, it seems that a concomitant
use of strong lipopolysaccharide antigen (a component of the
whole-cell pertussis) and thimerosal exerted serious synergistic
adverse health effects when given to individuals with latent central
nervous system T. gondii infection [184,340]. It is not clear,
however, whether the incidence of pertussis correlates with
intensity of DPT vaccination.
Childhood cluster diseases. The regression coefficient was
high (B = 4.24), and it explained 4.9% of variability (p = 0.041).
The high regression coefficient is not surprising because, for
example, respiratory tract diseases are the most frequent cause of
hospitalization and death in children and T. gondii infection is
extensively prevalent worldwide [148,367].
There are many predisposing, provocative, facilitating, and
other factors, such as chronic hypoxia, viral infections/bacterial
toxins, inflammatory states, biochemical disorders, and genetic
abnormalities that are the most likely triggers of development of
respiratory tract diseases, including sudden infant death syndrome
[368]. For example, exposure of children to cigarette smoke
(second-hand) increased their susceptibility to viral and bacterial
infections because children who died of sudden infant death
syndrome had markedly higher concentration of cotinine (a
metabolite of nicotine) in their lung tissue and pericardial fluid
than in controls [369,370]. Thus, negative effects of latent
toxoplasmosis on children’s physiology, including function of the
immune system, may markedly affect clinical course of diseases in
children and might significantly affect disease severity and
mortality.
Suicides. Latent toxoplasmosis was found to be associated
with an increased risk of attempted suicides [161,170,171,371].
The results of earlier correlation studies performed for 17–20
European countries [172,173] were confirmed by the present
study, wherein a positive trend was observed for the 29 European
countries (B = 4.05, p = 0.065, Eta
2
= 0.135), but, this correlation
could not be detected for the entire 88 countries. In fact, a
negative correlation between risk of suicide and prevalence of
latent toxoplasmosis was found for the 59 non-European countries
(B = 22.157, p = 0.012, Eta
2
= 0.11). We have no explanation for
this qualitative difference between European and non-European
countries. However, the existence of positive correlation between
the prevalence of latent toxoplasmosis and violence [174] was
confirmed by partial Kendall correlation for all countries
(Tau = 0.244, p = 0.001) and non-European countries
(Tau = 0.276, p = 0.002), but not for European countries
(Tau = 0.065, p = 0.619), the GLM method showed just a trend
for European countries (see tables shown in Fig. 3 and Fig. 4).
Traffic accidents. On the basis of four published case-
control studies, a positive correlation was expected between the
burden of traffic accidents and prevalence of latent toxoplasmosis.
However, this correlation was significant in nonparametric tests
(mortality: Tau = 0.148, p = 0.042; DALY: Tau = 0.164,
p = 0.023). Weak correlation in other tests may be caused by the
fact that the traffic accident rates depend on many confounding
variables, including the number of vehicles in circulation, length of
the road network, mean number of kilometers (miles) travelled by
one inhabitant per year, driver behavior (alcohol/drug use, sleep
deprivation, etc.), etc. Probably, much stronger correlations would
be detected when these variables would be included into the
models. Interestingly, the strongest association of latent toxoplas-
mosis and traffic accidents was found for RhD negative drivers
[372], while the RhD positive subjects, especially RhD positive
heterozygotes seem to be relatively protected against impairment
of reaction times [373,374] as well as against traffic accidents [372]
Correlation of Toxoplasmosis with Disease Burden
PLOS ONE | www.plosone.org 14 March 2014 | Volume 9 | Issue 3 | e90203
(the RhD refers to ‘‘Rhesus factor’’ with immunogenic D antigen,
while RhAG indicates no Rh antigens on red blood cell
membranes). The lack or deficiency of RhAG proteins in the host
red blood cell membrane and an impaired function of aquaporin
P1 and P4 water/gas channels in the central nervous system could
be associated with various degrees of brain hypoxia [339], thus
affecting usual driving performance possibly in synergy with the
effects of toxoplasmosis on reaction times and ability of long-term
concentration [3732375]. Since RhD negative individuals are
rare in African and Asian populations [376], an association
between traffic accidents and prevalence of toxoplasmosis can be
expected mainly in countries inhabited by Caucasians.
Limitations of the study
It is possible that some of the toxoplasmosis prevalence data are
inaccurate, as there are no published national survey data of latent
toxoplasmosis carried out systematically. In addition, surveys
performed in a relatively small, and ethnically and sociologically
homogeneous population, such as in the Czech Republic,
demonstrate that seroprevalence of toxoplasmosis varies consider-
ably in different regions of the country. Therefore, it is difficult to
estimate the average prevalence of this clinical entity in women of
child-bearing age in a particular country on the basis of one or two
studies performed in one hospital or even in one city. Further-
more, it is important to point out that the different serological
methods used to obtain toxoplasmosis seroprevalence data are not
standardized, and vary in sensitivity, specificity, and predictive
values. As a consequence, no two tests produce the same results in
all cases, even when carried out in the same laboratory [5].
For the present study, probably most of available data for the
period 1995–2008 were collected, and published information for
period prior to 1995 was also considered. To maximally avoid
possible subjective bias, we completed our data set on January
2013 and did not change it after starting the analyses despite of the
fact that data for other four countries appeared during 2013. To
further decrease the risk of subjectivity in selection of countries, we
included available data for all countries; our data set contained the
prevalence of toxoplasmosis in 88 countries, which represented the
largest ever data set analyzed in all toxoplasmosis correlation
studies. To increase the reliability of our results, we confirmed the
results of parametric GLM analysis with the nonparametric
Kendall test, which is less sensitive to contamination of data with
few incorrect values. It may be noted that lack of precision in the
prevalence data increases the risk of false negative but not false
positive results of correlation.
The existence of a factor correlating with both the prevalence of
latent toxoplasmosis and the disease burden can lead to a false
positive value in correlation studies. We controlled for one
potential confounding variable (GDP) in partial Kendall test and
for three potential confounding variables (GDP, latitude and
humidity) in GLM tests. It is possible that some unknown factor(s),
such as hygienic or eating habits, could influence both the
prevalence of latent toxoplasmosis and incidence or morbidity of
certain diseases. Existence of such factor(s) could be revealed by
confirming present analyses with another set of countries. In the
present study, data from all 88 countries were analyzed, and also
separately for the European and non-European countries. It is
important to repeat the correlation studies based upon indepen-
dent data sets (if available) for particular regions (such as in France)
or various states (such as in USA).
It is quite probable that the incidence of particular diseases
reflects better the prevalence of latent toxoplasmosis in an
unknown past, rather than the present prevalence. In many
countries, the prevalence of latent toxoplasmosis in young women
is changing: in some cases it is increasing (China, Korea and
Mexico) and in some it is decreasing (most of European countries
and USA). The prevalence of latent toxoplasmosis in a general
population (the parameter which probably better correlates with
disease burden) is more stable because it reflects past rather than
present epidemiological situation in particular countries. Still, our
lack of knowledge of optimal interval between toxoplasmosis
survey and disease burden surveys increases the risk of false
negative results of the obtained correlation studies.
Conclusions
The present results suggest that the prevalence of latent
toxoplasmosis in particular countries correlated (mostly positively)
with various disease burden measured with age standardized
Disability Adjusted Life Years or with age standardized mortality.
It must be emphasized that no epidemiological study and
especially no correlation (ecological) study can prove existence of
causal relation between the two factors. At the same time, results of
such studies could indicate which hypothesis should be tested in
the future. It is highly probable that some of the observed
correlations represent ‘‘false correlations’’ – either the Type 1
errors of used statistical tests or the expression of existence of
unknown factor(s) that correlates with both the risk of latent
toxoplasmosis and incidence (or severity) of particular disease.
However, it is also highly probable that at least some of the
observed correlations do occur because toxoplasmosis is, up to
now rarely suspected, etiological agent of particular diseases.
Existence of some correlations could be expected to happen on the
basis of our present knowledge for certain diseases (for example,
epilepsy, obsessive compulsive disorder, congenital abnormalities).
Some of the obtained correlations may be regarded as rather
surprising and should therefore be studied in more detail in the
future. In the opinion of the authors, slowly emerging important
role of latent toxoplasmosis in etiology of several clinical entities
deserves much more attention and financial support in future
clinical research.
Author Contributions
Conceived and designed the experiments: JF. Analyzed the data: JF.
Contributed reagents/materials/analysis tools: JF. Wrote the paper: JF JP
ZI. Data collection: MS.
References
1. Nicolle C, Manceaux L (1908) Sur une infection a` corps de Leishman (ou
organismes voisins) du gondi. C R Acad Sci (Paris) 147: 763–766.
2. Furtado JM, Smith JR, Belfort R, Jr., Gattey D, Winthrop KL (2011)
Toxoplasmosis: a global threat. J Glob Infect Dis 3: 281–284.
3. Dubey JP, Beattie CP (1988) Toxoplasmosis of animals and man. Boca Raton,
Fla.: CRC Press. pp. 1–220.
4. Dubey JP (1998) Advances in the life cycle of Toxoplasma gondii. Int J Parasitol
28: 1019–1024.
5. Tenter AM, Heckeroth AR, Weiss LM (2000) Toxoplasma gondii: from animals to
humans. Int J Parasitol 30: 1217–1258.
6. Jones JL, Kruszon-Moran D, Wilson M, McQuillan G, Navin T, et al. (2001)
Toxoplasma gondii infection in the United States: Seroprevalence and risk factors.
Am J Epidemiol 154: 357–365.
7. Scallan E, Hoekstra RM, Angulo FJ, Tauxe RV, Widdowson MA, et al. (2011)
Foodborne illness acquired in the United States-major pathogens. Emerg Infect
Dis 17: 7–15.
8. Pawłowski Z (1994) Toxoplasmosis. In: Januszkiewicz J, editor. The outline of
infectious diseases in the clinic. 2nd ed. Warsaw: PZWL. pp. 214–218.
9. Lafferty KD (2006) Can the common brain parasite, Toxoplas ma gondii, influence
human culture? Proc R Soc Biol Sci Ser B 273: 2749–2755.
Correlation of Toxoplasmosis with Disease Burden
PLOS ONE | www.plosone.org 15 March 2014 | Volume 9 | Issue 3 | e90203
10. Maggi P, Volpe A, Carito V, Schinaia N, Bino S, et al. (2009) Surveillance of
toxoplasmosis in pregnant women in Albania. New Microbiol 32: 89–92.
11. Rickard E, Costagliola M, Outen E, Cicero M, Garcia G, et al. (1999)
Toxoplasmosis antibody prevalence in pregnancy in Buenos Aires Province,
Argentina. Clin Microbiol Infec 5 171–1721.
12. Karunajeewa H, Siebert D, Hammond R, Garland S, Kelly H (2001)
Seroprevalence of varicella zoster virus, parvovirus B19 and Toxoplasma gondii in a
Melbourne obstetric population: implications for management. Aust N Z J Obstet
Gynaecol 41: 23–28.
13. Moese JR, Vander-Moese A (1998) Mother-child pass in Austria and primary
toxoplasmosis infections in pregnant women. Cent Eur J Public Health 6: 261–
264.
14. Tabbara KS, Saleh F (2005) Serodiagnosis of toxoplasmosis in Bahrain. Saudi
Med J 26: 1383–1387.
15. Ashrafunnessa, Shahla K, Islam MN, Huq T (1998) Seroprevalence of
Toxoplasma antibodies among the antenatal population in Bangladesh. J Obstet
Gynaecol Res 24.
16. Breugelmans M, Naessens A, Foulon W (2004) Prevention of toxoplasmosis
during pregnancy—an epidemiologic survey over 22 consecutive years.
J Perinat Med 32: 211–214.
17. Rodier MH, Berthonneau J, Bourgoin A, Giraudeau G, Agius G, et al. (1995)
Seroprevalences of Toxoplasma, malaria, rubella, cytomegalovirus, HIV and
treponemal infections among pregnant women in Cotonou, Republic of Benin.
Acta Trop 59: 271–277.
18. Fonseca AL, Silva RA, Fux B, Madureira AP, de Sousa FF, et al. (2012)
Epidemiologic aspects of toxoplasmosis and evaluation of its seroprevalence in
pregnant women. Rev Soc Bras Med Trop 45: 357–364.
19. Simpore J, Savadogo A, Ilboudo D, Nadambega MC, Esposito M, et al. (2006)
Toxoplasma gondii, HCV, and HBV seroprevalence and co-infection among
HIV-positive and -negative pregnant women in Burkina Faso. J Med Virol 78:
730–733.
20. Ndumbe PM, Andela A, Nkemnkengasong J, Watonsi E, Nyambi P (1992)
Prevalence of infections affecting the child among pregnant women in
Yaounde, Cameroon. Med Microbiol Immunol (Berl) 181: 127–130.
21. Many A, Koren G (2006) Toxoplasmosis during pregnancy. Can Fam
Physician 52: 29–30, 32.
22. Rosso F, Les JT, Agudelo A, Villalobos C, Chaves JA, et al. (2008) Prevalence
of infection with Toxoplasma gondii among pregnant women in Cali, Colombia,
South America. Am J Trop Med Hyg 78: 504–508.
23. Arias ML, Chinchilla M, Reyes L, Linder E (1996) Seroepidemiology of
toxoplasmosis in humans: possible transmission routes in Costa Rica. Rev Biol
Trop 44: 377–381.
24. Punda-Polic V, Tonkic M, Capkun V (2000) Prevalence of antibodies to
Toxoplasma gondii in the female population of the County of Split Dalmatia,
Croatia. Eur J Epidemiol 16: 875–877.
25. Sanchez-Gutierrez A, Martin-Herna ndez I, Garcia-Izquierdo SM (2003)
Estudio de reactividad a Toxoplasma gondii en embarazadas de las provincias
Ciudad de la Habana y Pinar del Rı
´o, Cuba. Lab Enferm Infec 28: 3–8.
26. Kan
ˇkova´S
ˇ, Flegr J (2007) Longer pregnancy and slower fetal development in
women with latent ‘‘asymptomatic’’ toxoplasmosis BMC Infect Dis 7: art: 114.
27. Makuwa M, Lecko M, Nsimba B, Bakouetela J, Lounana-Kouta J (1992)
Toxoplasmose et al femme enceinte au Congo Bilan de 5 ans de de´pistage
(1986–1990). Med Afr Noire 39: 493–495.
28. Lebech M, Andersen O, Christensen NC, Hertel J, Nielsen HE, et al. (1999)
Feasibility of neonatal screening for Toxoplasma infection in the absence of
prenatal treatment. Lancet 353: 1834–1837.
29. Attia RA, el-Zayat MM, Rizk H, Motawea S (1995) Toxoplasma IgG. & IgM.
antibodies. A case control study. J Egypt Soc Parasitol 25: 877–882.
30. Birgisdottir A, Asbjornsdottir H, Cook E, Gislason D, Jansson C, et al. (2006)
Seroprevalence of Toxoplasma gondii in Sweden, Estonia and Iceland.
Scand J Infect Dis 38: 625–631.
31. Dubey JP, Tiao N, Gebreyes WA, Jones JL (2 012) A review of toxoplasmosis in
humans and animals in Ethiopia. Epidemiol Infect 140: 1935–1938.
32. Koskiniemi M, Lappalainen M, Koskela P, Hedman K, Ammala P, et al.
(1992) The program for antenatal screening of toxoplasmosis in Finland: a
prospective cohort study. Scand J Infect Dis Suppl 84: 70–74.
33. Ancelle T, Goulet V, Tirard-Fleury V (2003) La toxoplasmose en France chez
la femme enceinte en 2003: se´ropre´ valence et facteurs associe´s. Bull Epidemiol
Hebd 51: 227–229.
34. Nabias R, Ngouamizokou A, Migot-Nabias F, Mbou-Moutsimbi RA, Lansoud-
Soukate J (1998) [Serological investigation of toxoplasmosis in patients of the
M.I.P. center of Franceville (Gabon)]. Bull Soc Pathol Exot Filial 91: 318–320.
35. Fiedler K, Hulsse C, Straube W, Briese V (1999) [Toxoplasmosis-antibody
seroprevalence in Mecklenburg-Western Pomerania]. Zentralbl Gynakol 121:
239–243.
36. Antoniou M, Tzouvali H, Sifakis S, Galanakis E, Georgopoulou E, et al. (2004)
Incidence of toxoplasmosis in 5532 pregnant women in Crete, Greece:
management of 185 cases at risk. Eur J Obstet Gynecol Reprod Biol 117: 138–
143.
37. Asthana SP, Macpherson CN, Weiss SH, Stephens R, Denny TN, et al. (2006)
Seroprevalence of Toxoplasma gondii in pregnant women and cats in Grenada,
West Indies. J Parasitol 92: 644–645.
38. Szenasi Z, Horvath K, Sarkany E, Melles M (2005) Toxoplasmosis surveillance
during pregnancy and quality assurance of methods in Hungary. Wien Klin
Wochenschr 117: 29–34.
39. Contreras MC, Schenone H, Salinas P, Sandoval L, Rojas A, et al. (2009)
Seroepidemiology of human toxoplasmosis in Chile. Rev Inst Med Trop Sao
Paulo 38: 431–435.
40. Liu Q, Wei F, Gao SY, Jiang L, Lian H, et al. (2009) Toxoplasma gondii infection
in pregnant women in China. T Roy Soc Trop Med H 103: 162–166.
41. Borkakoty BJ, Borthakur AK, Gohain M (2007) Prevalence of Toxoplasma gondii
infection amongst pregnant women in Assam, India. Indian J Med Microbiol
25: 431–432.
42. Konishi E, Houki Y, Harano K, Mibawani RS, Marsudi D, et al. (2000) High
prevalence of antibody to Toxoplasma gondii among humans in Surabaya,
Indonesia. Japanese J Infect Dis 53: 238–241.
43. Fallah M, Rabiee S, Matini M, Taherkhani H (2008) Seroepidemiology of
toxoplasmosis in primigravida women in Hamadan, Islamic Republic of Iran,
2004. East Mediterr Health J 14: 163–171.
44. Mahdi NK, Sharief M (2002) Risk factors for acquiring toxoplasmosis in
pregnancy. J Bahrain Med Soc 14: 148–151.
45.FergusonW,MaynePD,LennonB,ButlerK,CafferkeyM(2008)
Susceptibility of pregnant women to Toxoplasma infection—potential benefits
for newborn screening. Ir Med J 101: 220–221.
46. Franklin DM, Dror Z, Nishri Z (1993) The prevalence and incidence of
Toxoplasma antibodies in pregnant women. Isr J Med Sci 29: 285–286.
47. De Paschale M, Agrappi C, Clerici P, Mirri P, Manco MT, et al. (2008)
Seroprevalence and incidence of Toxoplasma gondii infection in the Legnano area
of Italy. Clin Microbiol Infect 14: 186–189.
48. Prabhakar P, Bailey A, Smikle MF, McCaw-Binns A, Ashley D (1991)
Seroprevalence of Toxoplasma gondii, rubella virus, cytomegalovirus herpes
simplex virus (TORCH) and syphilis in Jamaican pregnant women. West
Indian Med J 40: 166–169.
49. Sakikawa M, Noda S, Hanaoka M, Nakayama H, Hojo S, et al. (2012) Anti-
Toxoplasma antibody prevalence, primary infection rate, and risk factors in a
study of toxoplasmosis in 4,466 pregnant women in Japan. Clin Vaccin
Immunol 19: 365–367.
50. Jumaian NF (2005) Seroprevalence and risk factors for Toxoplasma infection in
pregnant women in Jordan. East Mediterr Health J 11: 45–51.
51. Iqbal J, Hira PR, Khalid N (2003) Toxoplasmosis in Kuwait: improved
diagnosis based on quantitative immuno-assay. Clin Microbiol Infect 9: 336.
52. Szenasi Z, Ozsvar Z, Nagy E, Jeszenszky M, Szabo J, et al. (1997) Prevention of
congenital toxoplasmosis in Szeged, Hungary. Int J Epidemiol 26: 428–435.
53. Mousa DA, Mohammad MA, Toboli AB (2011) Toxoplasma gondii infection in
pregnant women with previous adverse pregnancy outcome. Med J Islam
World Acad Sci 19: 95–102.
54. Rockiene L (1997) The prognosis of congenital toxoplasmosis in Lithuania.
Hygiena Epidemiol 58: 39–45.
55. Bobic B, Nikolic A, Klun I, Djurkovic-Djakovic O (2011) Kinetics of Toxoplasma
infection in the Balkans. Wien Klin Wochenschr 123: 2–6.
56. Lelong B, Rahelimino B, Candolfi E, Ravelojaona BJ, Villard O, et al. (1995)
[Prevalence of toxoplasmosis in a population of pregnant women in
Antananarivo (Madagascar)]. Bull Soc Pathol Exot Filial 88: 46–49.
57. Nissapatorn V, Noor Azmi MA, Cho SM, Fong MY, Init I, et al. (2003)
Toxoplasmosis: prevalence and risk factors. J Obstet Gynaecol 23: 618–624.
58. Caballero-Ortega H, Uribe-Salas FJ, Conde-Glez CJ, Cedillo-Pelaez C,
Vargas-Villavicencio JA, et al. (2012) Seroprevalence and national distribution
of human toxoplasmosis in Mexico: analysis of the 2000 and 2006 National
Health Surveys. T Roy Soc Trop Med H 106: 653–659.
59. El Mansouri B, Rhajaoui M, Sebti F, Amarir F, Laboudi M, et al. (2007)
[Seroprevalence of toxoplasmosis in pregnant women in Rabat, Morocco]. Bull
Soc Pathol Exot Filial 100: 289–290.
60. Sitoe SP, Rafael B, Meireles LR, Andrade HF, Jr., Thompson R (2010)
Preliminary report of HIV and Toxoplasma gondii occurrence in pregnant women
from Mozambique. Rev Inst Med Trop Sao Paulo 52: 291–295.
61. Rai SK, Shibata H, Sumi K, Rai G, Rai N, et al. (1998) Toxoplasma antibody
prevalence in Nepalese pregnant women and women with bad obstetric history.
Southeast Asian J Trop Med Public Health 29: 739–743.
62. Kortbeek LM, De Melker HE, Veldhuijzen IK, Conyn-Van Spaendonck MA
(2004) Population-based Toxoplasma seroprevalence study in The Netherlands.
Epidemiol Infect 132: 839–845.
63. Morris A, Croxson M (2004) Serological evidence of Toxoplasma gondii infection
among pregnant women in Auckland. N Z Med J 117: U770.
64. Onadeko MO, Joynson DH, Payne RA (1992) The prevalence of Toxoplasma
infection among pregnant women in Ibadan, Nigeria. J Trop Med Hyg 95:
143–145.
65. Jenum PA, Kapperud G, Stray-Pedersen B, Melby KK, Eskild A, et al. (1998)
Prevalence of Toxoplasma gondii specific immunoglobulin G antibodies among
pregnant women in Norway. Epidemiol Infect 120: 87–92.
66. Ahmed MU, Hafiz A (1997) Toxoplasmosis and abortion: serological
correlation. J Coll Phys Surg Pak 7: 156–159.
67. Klufio CA, Delamare O, Amoa AB, Kariwiga G (1993) The prevalence of
Toxoplasma antibodies in pregnant patients attending the Port Moresby General
Hospital antenatal clinic: a seroepidemiological survey. P N G Med J 36: 4–9.
68. Cantella R, Colichon A, Lopez L, Wu C, Goldfarb A, et al. (1974)
Toxoplasmosis in Peru. Geographic prevalence of Toxoplasma gondii antibodies
Correlation of Toxoplasmosis with Disease Burden
PLOS ONE | www.plosone.org 16 March 2014 | Volume 9 | Issue 3 | e90203
in Peru studied by indirect fluorescent antibody technique. Trop Geogr Med
26: 204–209.
69. Nowakowska D, Stray-Pedersen B, Spiewak E, Sobala W, Malafiej E, et al.
(2006) Prevalence and estimated incidence of Toxoplasma infection among
pregnant women in Poland: a decreasing trend in the younger population. Clin
Microbiol Infec 12: 913–917.
70. Lopes AP, Dubey JP, Moutinho O, Gargate MJ, Vilares A, et al. (2012)
Seroepidemiology of Toxoplasma gondii infection in women from the North of
Portugal in their childbearing years. Epidemiol Infect 140: 872–877.
71. Abu-Madi MA, Behnke JM, Dabritz HA (2010) Toxoplasma gondii seropositivity
and co-infection with TORCH pathogens in high-risk patients from Qatar.
Am J Trop Med Hyg 82: 626–633.
72. Lim H, Lee SE, Jung BK, Kim MK, Lee MY, et al. (2012) Serologic survey of
toxoplasmosis in Seoul and Jeju-do, and a brief review of its seroprevalence in
Korea. Korean J Parasitol 50: 287–293.
73. Crucerescu E (1998) [Epidemiological data on toxoplasmosis. The aspects of
congenital toxoplasmosis]. Bacteriol Virusol Parazitol Epidemiol 43: 147–155.
74. Hung CC, Fan CK, Su KE, Sung FC, Chiou HY, et al. (2007) Serological
screening and toxoplasmosis exposure factors among pregnant women in the
Democratic Republic of Sao Tome and Principe. Trans R Soc Trop Med Hyg
101: 134–139.
75. el Hady HM (1991) Toxoplasmosis among pregnant women in Abha, Saudi
Arabia. J Egypt Soc Parasitol 21: 811–815.
76. Faye O, Leye A, Dieng Y, Richard-Lenoble D, Diallo S (1998) [Toxopl asmosis
in Dakar. Seroepidemiologic sampling of 353 women of reproductive age]. Bull
Soc Pathol Exot Filial 91: 249–250.
77. Wong A, Tan KH, Tee CS, Yeo GS (2000) Seroprevalence of cytomegalovirus,
Toxoplasma and parvovirus in pregnancy. Singapore Med J 41: 151–155.
78. Studenicova C, Ondriska F, Holkova R (2008) [Seroprevalence of Toxoplasma
gondii among pregnant women in Slovakia]. Epidemiol Mikrobiol Imunol 57:
8–13.
79. Logar J, Petrovec M, Novak-Antolic Z, Premru-Srsen T, Cizman M, et al.
(2002) Prevention of congenital toxoplasmosis in Slovenia by serological
screening of pregnant women. Scand J Infect Dis 34: 201–204.
80. Munoz Batet C, Guardia Llobet C, Juncosa Morros T, Vinas Domenech L,
Sierra Soler M, et al. (2004) [Toxoplasmosis and pregnancy. Multicenter study
of 16,362 pregnant women in Barcelona]. Med Clin (Barc) 123: 12–16.
81. Elnahas A, Gerais AS, Elbashir MI, Eldien ES, Adam I (2003) Toxoplasmosi s
in pregnant Sudanese women. Saudi Med J 24: 868–870.
82. Evengard B, Petersson K, Engman ML, Wiklund S, Ivarsson SA, et al. (2001)
Low incidence of Toxoplasma infection during pregnancy and in newborns in
Sweden. Epidemiol Infect 127: 121–127.
83. Signorell LM, Seitz D, Merkel S, Berger R, Rudin C (2006) Cord blood
screening for congenital toxoplasmosis in northwestern Switzerland, 1982–
1999. Pediatr Infect Dis J 25: 123–128.
84. Doehring E, Reiter-Owona I, Bauer O, Kaisi M, Hlobil H, et al. (1995)
Toxoplasma gondii antibodies in pregnant women and their newborns in Dar es
Salaam, Tanzania. Am J Trop Med Hyg 52: 546–548.
85. Deniau M, Tourte-Schaefer C, Agbo K, Dupouy-Cam et J, Heyer C, et al.
(1991) E
´valuation des risques de toxoplasmose conge´nitale au Togo. Bull Soc
Pathol Exot Filial 84: 664–672.
86. Ramsewak S, Gooding R, Ganta K, Seepersadsingh N, Adesiyun AA (2008)
Seroprevalence and risk factors of Toxoplasma gondii infection among pregnant
women in Trinidad and Tobago. Rev Panam Salud Publica 23: 164–170.
87. Ndong-Obame T, Ayadi A (1997) La toxoplasmose acquise et conge´nitale dans
la re´ gion de Sfax (Tunisie). Bull Soc Fr Parasitol 15: 141–147.
88. Harma M, Gungen N, Demir N (2004) Toxoplasmosis in pregnant women in
Sanliurfa, Southeastern Anatolia City, Turkey. J Egypt Soc Parasitol 34: 519–
525.
89. Dar FK, Alkarmi T, Uduman S, Abdulrazzaq Y, Gru ndsell H, et al. (1997)
Gestational and neonatal toxoplasmosis: regional seroprevalence in the United
Arab Emirates. Eur J Epidemiol 13: 567–571.
90. Nash JQ, Chissel S, Jones J, Warburton F, Verlander NQ (2005) Risk factors
for toxoplasmosis in pregnant women in Kent, United Kingdom. Epidemiol
Infect 133: 475–483.
91. Jones JL, Kruszon-Moran D, Sanders-Lewis K, Wilson M (2007) Toxoplasma
gondii infection in the United States, 1999-2004, decline from the prior decade.
Am J Trop Med Hyg 77: 405–410.
92. Triolo-Mieses M, Traviezo-Valles L (2006) Serological prevalence of
Toxoplasma gondii antibodies in pregnancy in Palavecino Municipality Lara
State,Venezuela. Kasmera 34: 7–13.
93. Buchy P, Follezou JY, Lien TX, An TT, Tram LT, et al. (2003) [Serological
study of toxoplasmosis in Vietnam in a population of drug users (Ho Chi Minh
city) and pregnant women (Nha Trang)]. Bull Soc Pathol Exot Filial 96: 46–47.
94. Kodym P, Maly´M,S
ˇvandova´ E, Lekatkova´ H, Badoutova´ M, et al. (2000)
Toxoplasma in the Czech Republic 1923–1999: first case to widespread
outbreak. Int J Parasitol 30: 11–18.
95. Walton BC, De Arjona I, Benchoff BM (1966) Relationship of Toxoplasma
antibodies to altitude. Am J Trop Med Hyg 15: 492–495.
96. Jokelainen P, Nareaho A, Knaapi S, Oksanen A, Rikula U, et al. (2010)
Toxoplasma gondii in wild cervids and sheep in Finland: north-south gradient in
seroprevalence. Vet Parasitol 171: 331–336.
97. Akanmu AS, Osunkalu VO, Ofomah JN, Olowo selu FO (2010) Pattern of
demographic risk factors in the seropreva lence of anti-Toxoplasma gondii
antibodies in HIV infected patients at the Lagos University Teaching Hospital.
Nig Q J Hosp Med 20: 1–4.
98. Addebbous A, Adarmouch L, Tali A, Laboudi M, Amine M, et al. (2012) IgG
anti-Toxoplasma antibodies among asymptomatic HIV-infected patients in
Marrakesh-Morocco. Acta Trop 123: 49–52.
99. Weight CM, Carding SR (2012) The protozoan pathogen Toxoplasma gondii
targets the paracellular pathway to invade the intestinal epithelium.
Ann N Y Acad Sci 1258: 135–142.
100. Lindsay DS, Dubey JP (2011) Toxoplasma gondii: the changing paradigm of
congenital toxoplasmosis. Parasitology 138: 1829–1831.
101. Carneiro AC, Andrade GM, Costa JG, Pinheiro BV, Vasconcelos-Santos DV,
et al. (2013) Genetic characterization of Toxoplasma gondii revealed highly
diverse genotypes for isolates from newborns with congenital toxoplasmosis in
southeastern Brazil. J Clin Microbiol 51: 901–907.
102. Araujo FG, Slifer T (2003) Different strains of Toxoplasma gondii induce different
cytokine responses in CBA/Ca mice. Infect Immun 71: 4171–4174.
103. Nelson MM, Jones AR, Carmen JC, Sinai AP, Burchmore R, et al. (2008)
Modulation of the host cell proteome by the intracellular apicomplexan
parasite Toxoplasma gondii. Infect Immun 76: 828–844.
104. Thirugnanam S, Rout N, Gnanasekar M (2013) Possible role of Toxoplasma
gondii in brain cancer through modulation of host microRNAs. Infect Agent
Cancer 8: 8.
105. Dubey JP, Ferreira LR, Martins J, McLeod R (2012) Oral oocyst-induced
mouse model of toxoplasmosis: effect of infection with Toxoplasma gondii strains
of different genotypes, dose, and mouse strains (transgenic, out-bred, in-bred)
on pathogenesis and mortality. Parasitology 139: 1–13.
106. McLeod R, Boyer KM, Lee D, Mui E, Wroblewski K, et al. (2012) Prematurity
and severity are associated with Toxoplasma gondii alleles (NCCCTS, 1981–
2009). Clin Infect Dis 54: 1595–1605.
107. Khan A, Fux B, Su C, Dubey JP, Darde ML, et al. (2007) Recent
transcontinental sweep of Toxoplasma gondii driven by a single monomorphic
chromosome. Proc Natl Acad Sci USA 104: 14872–14877.
108. Mercier A, Devillard S, Ngoubangoye B, Bonnabau H, Banuls AL, et al. (2010)
Additional haplogroups of Toxoplasma gondii out of Africa: population structure
and mouse-virulence of strains from Gabon. PLoS Neglect Trop D 4: e876.
109. Khan A, Jordan C, Muccioli C, Vallochi AL, Rizzo LV, et al. (2006) Genetic
divergence of Toxoplasma gondii strains associated with ocular toxoplasmosis,
Brazil. Emerg Infect Dis 12: 942–949.
110. Glasner PD, Silveira C, Kruszon-Moran D, Martins MC, Burnier Junior M, et
al. (1992) An unusually high prevalence of ocular toxoplasmosis in southern
Brazil. Am J Ophthalmol 114: 136–144.
111. Frenkel JK (1953) Host, strain and treatment variation as factors in the
pathogenesis of toxoplasmosis. Am J Trop Med Hyg 2: 390–415.
112. Jacobs L (1956) Propagation, morphology, and biology of Toxoplasma.
Ann N Y Acad Sci 64: 154–179.
113. Prestrud KW, Asbakk K, Oksanen A, Nareaho A, Jokelainen P (2010)
Toxoplasma gondii in the Subarctic and Arctic. Acta Vet Scand (Suppl. 1): 57.
114. Sroka J (2001) Seroepidemiology of toxoplasmosis in the Lublin region. Ann
Agric Environ Med 8: 25–31.
115. Petersen E, Vesco G, Villari S, Buffolano W (2010) What do we know about
risk factors for infection in humans with Toxoplasma gondii and how can we
prevent infections? Zoonoses Public Health 57: 8–17.
116. Alvarado-Esquivel C, Alanis-Quinones OP, Arreola-Valenzuela MA, Rodri-
guez-Briones A, Piedra-Nevarez LJ, et al. (2006) Seroepidemiology of
Toxoplasma gondii infection in psychiatric inpatients in a northern Mexican city.
BMC Infect Dis 6: 178.
117. Ferguson DJ (2009) Identification of faecal transmission of Toxoplasma gondii:
Small science, large characters. Int J Parasitol 39: 871–875.
118. Kolbekova´ P, Kourbatova E, Novotna´ M, Kodym P, Flegr J (2007) New and
old risk-factors for Toxoplasma gondii infection: prospective cross-sectional study
among military personnel in the Czech Republic. Clin Microbiol Infec 13:
1012–1017.
119. Jones JL, Dargelas V, Roberts J, Press C, Remington JS, et al. (2009) Risk
factors for Toxoplasma gondii infection in the United States. Clin Infect Dis 49:
878–884.
120. Yazar S, Eser B, Yay M (2006) Prevalence of anti-Toxoplasma gondii antibodies
in Turkish blood donors. Ethiop Med J 44: 257–261.
121. Elhence P, Agarwal P, Prasad KN, Chaudhary RK (2010) Seroprevalence of
Toxoplasma gondii antibodies in North Indian blood donors: Implications for
transfusion transmissible toxoplasmosis. Transfus Apher Sci 43: 37–40.
122. Silveira C, Vallochi AL, da Silva UR, Muccioli C, Holland GN, et al. (2011)
Toxoplasma gondii in the peripheral blood of patients with acute and chronic
toxoplasmosis. Br J Ophthalmol 95: 396–400.
123. Hafid J, Bellete B, Flori P, Sawadogo P, Boyer Y (2005) Materno-foetal
transmission of murine toxoplasmosis after oral infection. Am J Immunol 1: 1–
5.
124. Schroder J, Tiilikainen A, De la Chapelle A (1974) Fetal leukocytes in the
maternal circulation after delivery. I. Cytological aspects. Transplantation 17:
346–354.
125. Fischer SA (2006) Infections complicating solid organ transplantation. Surg
Clin North Am 86: 1127–1145, v-vi.
126. Derouin F, Pelloux H (2008) Prevention of toxoplasmosis in transplant patients.
Clin Microbiol Infect 14: 1089–1101.
Correlation of Toxoplasmosis with Disease Burden
PLOS ONE | www.plosone.org 17 March 2014 | Volume 9 | Issue 3 | e90203
127. Edvinsson B, Lundquist J, Ljungman P, Ringden O, Evengard B (2008) A
prospective study of diagnosis of Toxoplasma gondii infection after bone marrow
transplantation. APMIS 116: 345–351.
128. Fricker-Hidalgo H, Bulabois CE, Brenier-Pinchart MP, Hamidfar R, Garban
F, et al. (2009) Diagnosis of toxoplasmosis after allogeneic stem cell
transplantation: results of DNA detection and serological techniques. Clin
Infect Dis 48: e9–e15.
129. Laibe S, Ranque S, Curtillet C, Faraut F, Dumon H, et al. (2006) Timely
diagnosis of disseminated toxoplasmosis by sputum examination. J Clin
Microbiol 44: 646–648.
130. Hiramoto RM, Mayrbaurl-Borges M, Galisteo AJ, Jr., Meireles LR, Macre
MS, et al. (2001) Infectivity of cysts of the ME-49 Toxoplasma gondii strain in
bovine milk and homemade cheese. Rev Saude Publica 35: 113–118.
131. Camossi LG, Greca-Junior H, Correa AP, Richini-Pereira VB, Silva RC, et al.
(2011) Detection of Toxoplasma gondii DNA in the milk of naturally infected
ewes. Vet Parasitol 177: 256–261.
132. Arantes TP, Lopes WDZ, Ferreira RM, Pieroni JSP, Pinto VMR, et al. (2009)
Toxoplasma gondii: Evidence for the transmission by semen in dogs. Exp Parasitol
123: 190–194.
133. Singh S, Singh N (1993) Toxoplasmosis is transmitted sexually. Int Conf AIDS
9: 490.
134. Elsheikha HM (2008) Congenital toxoplasmosis: Priorities for further health
promotion action. Public Health 122: 335–353.
135. Joiner KA, Dubremetz JF (1993) Toxoplasma gondii: a protozoan for the nineties.
Infect Immun 61: 1169–1172.
136. Channon JY, Seguin RM, Kasper LH (2000) Differential infectivity and
division of Toxoplasma gondii in human peripheral blood leukocytes. Infect
Immun 68: 4822–4826.
137. Lambert H, Hitziger N, Dellacasa I, Svensson M, Barragan A (2006) Induction
of dendritic cell migration upon Toxoplasma gondii infection potentiates parasite
dissemination. Cell Microbiol 8: 1611–1623.
138. Da Gama LM, Ribeiro-Gomes FL, Guimaraes U, Jr., Arnh oldt AC (2004)
Reduction in adhesiveness to extracellular matrix components, modulation of
adhesion molecules and in vivo migration of murine macrophages infected with
Toxoplasma gondii. Microbes Infect 6: 1287–1296.
139. Courret N, Darche S, Sonigo P, Milon G, Buzoni-Gatel D, et al. (2006)
CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma
gondii tachyzoites to the brain. Blood 107: 309–316.
140. Lambert H, Vutova PP, Adams WC, Lore K, Barragan A (2009) The
Toxoplasma gondii-shuttling function of dendritic cells is linked to the parasite
genotype. Infect Immun 77: 1679–1688.
141. Bierly AL, Shufesky WJ, Sukhumavasi W, Morelli AE, Denkers EY (2008)
Dendritic cells expressing plasmacytoid marker PDCA-1 are Trojan horses
during Toxoplasma gondii infection. J Immunol 181: 8485–8491.
142. Lambert H, Barragan A (2010) Modelling parasite dissemination: host cell
subversion and immune evasion by Toxoplasma gondii. Cell Microbiol 12: 292–
300.
143. Persson CM, Lambert H, Vutova PP, Dellacasa-Lindberg I, Nederby J, et al.
(2009) Transmission of Toxoplasma gondii from infected dendritic cells to natural
killer cells. Infect Immun 77: 970–976.
144. Nigro G, Piazze J, Paesano R, Mango T, Provvedi S, et al. (1999) Low levels of
natural killer cells in pregnant women transmitting Toxoplasma gondii. Prenat
Diagn 19: 401–404.
145. Montoya JG, Liesenfeld O (2004) Toxoplasmosis. Lancet 363: 1965–1975.
146. Vaillant V, de Valk H, Baron E, Ancelle T, Colin P, et al. (2005) Foodborne
infections in France. Foodborne Pathog Dis 2: 221–232.
147. Mead PS, Slutsker L, Dietz V, McCaig LF, Bresee JS, et al. (1999) Food-related
illness and death in the United States. Emerg Infect Dis 5: 607–625.
148. Klaren VNA, Kijlstra A (2002) Toxoplasmosis, an overview with emphasis on
ocular involvement. Ocul Immunol Inflamm 10: 1–26.
149. Havelaar AH, Kemmeren JM, Kortbeek LM (2007) Disease burden of
congenital toxoplasmosis. Clin Infect Dis 44: 1467–1474.
150. Gilbert RE, Stanford MR (2000) Is ocular toxoplasmosis caused by prenatal or
postnatal infection? Br J Ophthalmol 84: 224–226.
151. Jones JL, Holland GN (2010) Annual burden of ocular toxoplasmosis in the
US. Am J Trop Med Hyg 82: 464–465.
152. Porter SB, Sande MA (1992) Toxoplasmosis of the central nervous system in
the acquired immunodeficiency syndrome. N Engl J Med 327: 1643–1648.
153. Beaver PC, Jung RC, Cupp EW, Craig CF (1984) Clinical Parasitology.
Philadelphia: Lea & Febiger. viii, 825 p. p.
154. Carter CJ (2013) Toxoplasmosis and polygenic disease susceptibility genes:
extensive Toxoplasma gondii host/pathogen interactome enrichment in nine
psychiatric or neurological disorders. J Pathog 2013: 965046.
155. Ajzenberg D, Cogne N, Paris L, Bessieres MH, Thulliez P, et al. (2002)
Genotype of 86 Toxoplasma gondii isolates associated with human congenital
toxoplasmosis, and correlation with clinical findings. J Infect Dis 186: 684–689.
156. Weiss LM, Dubey JP (2009) Toxoplasmosis: A history of clinical observations.
Int J Parasitol 39: 895–901.
157. Robert-Gangneux F, Gangneux JP, Vu N, Jaillard S, Guiguen C, et al. (2011)
High level of soluble HLA-G in amniotic fluid is correlated with congenital
transmission of Toxoplasma gondii. Clin Immunol 138: 129–134.
158. Silveira C, Ferreira R, Muccioli C, Nussenblatt R, Belfort R (2003)
Toxoplamosis transmitted to a newborn from the mother infected 20 years
earlier. Am J Ophthalmol 136: 370–371.
159. Hinze-Selch D, Daubener W, Erdag S, Wilms S (2010) The diagnosis of a
personality disorder increases the likelihood for seropositivity to Toxoplasma
gondii in psychiatric patients. Folia Parasitol 57 129–135.
160. Zhu S (2009) Psychosis may be associated with toxoplasmosis. Med Hypotheses
73: 799–801.
161. Okusaga O, Langenberg P, Sleemi A, Vaswani D, Giegling I, et al. (2011)
Toxoplasma gondii antibody titers and history of suicide attempts in patients with
schizophrenia. Schizophr Res 133: 150–155.
162. Emelia O, Amal RN, Ruzanna ZZ, Shahida H, Azzubair Z, et al. (2012)
Seroprevalenc e of anti-Toxoplasma gondii IgG antibody in patients with
schizophrenia. Trop Biomed 29: 151–159.
163. Mortensen PB, Pedersen CB, McGrath JJ, Hougaard DM, Norgaard-Petersen
B, et al. (2011) Neonatal antibodies to infectious agents and risk of bipolar
disorder: a population-based case-control study. Bipolar Disorder 13: 624–629.
164. Blomstrom A, Karlsson H, Wicks S, Yang S, Yolken RH, et al. (2012) Maternal
antibodies to infectious agents and risk for non-affective psychoses in the
offspring—a matched case-control study. Schizophr Res 140: 25–30.
165. Tedla Y, Shibre T, Ali O, Tadele G, Woldeamanuel Y, et al. (2011) Serum
antibodies to Toxoplasma gondii and Herpesviridae family viruses in individuals
with schizophrenia and bipolar disorder: a case-control study. Ethiop Med J 49:
211–220.
166. Torrey EF, Bartko JJ, Lun ZR, Yolken RH (2007) Antibodies to Toxoplasma
gondii in patients with schizophrenia: A meta-analysis. Schizophr Bull 33: 729–
736.
167. Pearce BD, Kruszon-Moran D, Jones JL (2012) The relationship between
Toxoplasma gondii infection and mood disorders in the Third National Health
and Nutrition Survey. Biol Psychiatry 72: 290–295.
168. Groer MW, Yolken RH, Xiao JC, Beckstead JW, Fuchs D, et al. (2011)
Prenatal depression and anxiety in Toxoplasma gondii-positive women.
Am J Obstet Gynecol 204.
169. Radford A, Williams SN, Kane B, Groer M (2012) Relationships of Toxoplasma
antibody titers and dysphoric moods in female veterans. Brain, Behaviour, and
Immunity 26.
170. Yagmur F, Yazar S, Temel HO, Cavusoglu M (2010) May Toxoplasma gondii
increase suicide attempt - preliminary results in Turkish subjects? Forensic Sci
Int 199: 15–17.
171. Pedersen MG, Mortensen PB, Norgaard-Pedersen B, Postolache TT (2012)
Toxoplasma gondii infection and self-directed violence in mothers. Arch Gen
Psychiatry 69: 1123–1130.
172. Lester D (2010) Predicting European suicide rates with physiological indices.
Psychol Rep 107: 713–714.
173. Ling VJ, Lester D, Mortensen PB, Postolache TT (2011) Toxoplasm a gondii
seropositivity and completed suicide in 20 European countries. Biol Psychiatry
69: 500.
174. Lester D (2012) Toxoplasma gondii and homicide. Psychol Rep 111: 196–197.
175. Brynska A, Tomaszewicz-Libudzic E, Wolanczyk T (2001) Obsessive-
compulsive disorder and acquired toxoplasmosis in two children. Eur Child
Adolesc Psychiatry 10: 200–204.
176. Miman O, Mutlu EA, Ozcan O, Atambay M, Karlidag R, et al. (2010) Is there
any role of Toxoplasma gondii in the etiology of obsessive-compulsive disorder?
Psychiatry Res 177: 263–265.
177. Parness-Yossifon R, Margalit D, Pollack A, Leiba H (2008) Behavioral
disorders in children with idiopathic intracranial hypertension. J Child Neurol
23: 447–450.
178. Stahl W, Turek G (1988) Chronic murine toxoplasmosis: clinicopathologic
characterization of a progressive wasting syndrome. Ann Trop Med Parasitol
82: 35–48.
179. Arsenijevic D, Girardier L, Seydoux J, Pechere JC, Garcia I, et al. (1998)
Metabolic-cytokine responses to a second immunological challenge with LPS in
mice with T. gondii infection. Am J Physiol 274: E439–445.
180. Arsenijevic D, Bilbao FD, Giannakopoulos P, Girardier L, Samec S, et al.
(2001) A role for interferon-gamma in the hypermetabolic response to murine
toxoplasmosis. Eur Cytokine Netw 12: 518–527.
181. Arsenijevic D, Girardier L, Seydoux J, Chang HR, Dulloo AG (1997) Altered
energy balance and cytokine gene expression in a murine model of chronic
infection with Toxoplasma gondii American Journal of Physiology-Endocrinology
and Metabolism 35: 908–917.
182. Prandota J (2011) Metabolic, immune, epigenetic, endocrine and phenot ypic
abnormalities found in individuals with autism spectrum disorders, Down
syndrome and Alzheimer disease may be caused by congenital and/or acquired
chronic cerebral toxoplasmosis. Res Autism Spectr Disorders 5: 14–59.
183. Prandota J (2010) Autism spectrum disorders may be due to cereb ral
toxoplasmosis associated with chronic neuroinflammation causing persistent
hypercytokinemia that resulted in an increased lipid peroxidation, oxidative
stress, and depressed metabolism of endogenous and exogenous substances. Res
Autism Spectr Disorders 4: 119–155.
184. Prandota J (2009) Neuropathological changes and clinical features of autism
spectrum disorder participants are similar to that reported in congenital and
chronic cerebral toxoplasmosis in humans and mice. Res Autism Spectr
Disorders 4: 103–118.
185. Conley FK, Jenkins KA (1981) Immunohistological study of the anatomic
relationship of Toxoplasma antigens to the inflammatory response in the brains
of mice chronically infected with Toxoplasma gondii Infect Immun 31: 1184–
1192.
Correlation of Toxoplasmosis with Disease Burden
PLOS ONE | www.plosone.org 18 March 2014 | Volume 9 | Issue 3 | e90203
186. Ribeiro DA, Pereira PCM, Machado JM, Silva SB, Pessoa AWP, et al. (2004)
Does toxoplasmosis cause DNA damage? An evaluation in isogenic mice under
normal diet or dietary restriction. Mutat Res- Gen Tox En 559: 169–176.
187. Massimine KM, Doan LT, Atreya CA, Stedman TT, Anderson KS, et al.
(2005) Toxoplasma gondii is capable of exogenous folate transport - A likely
expansion of the BT1 family of transmembrane proteins. Mol Biochem
Parasitol 144: 44–54.
188. Al-Gazali LI, Padmanabhan R, Melnyk S, Yi P, Pogribny IP, et al. (2001)
Abnormal folate metabolism and genetic polymorphism of the folate pathway
in a child with Down syndrome and neural tube defect. Am J Med Genet 103:
128–132.
189. Rao AA, Sridhar GR, Das UN (2007) Elevated butyrylcholinesterase and
acetylcholinesterase may predict the development of type 2 diabetes mellitus
and Alzheimer’s disease. Med Hypotheses 69: 1272–1276.
190. Kusbeci OY, Miman O, Yaman M, Aktepe OC, Yazar S (2011) Could
Toxoplasma gondii have any role in Alzheimer disease? Alzheimer Dis Assoc
Disord 25: 1–3.
191. Chan WF, Gurnot C, Montine TJ, Sonnen JA, Guthrie KA, et al. (2012) Male
microchimerism in the human female brain. PLoS ONE 7: e45592.
192. Miman O, Kusbeci OY, Aktepe OC, Cetinkaya Z (2010) The probable
relation between Toxoplasma gondii and Parkinson’s disease. Neurosci Lett 475:
129–131.
193. Murakami T, Nakajima M, Nakamura T, Hara A, Uyama E, et al. (2000)
Parkinsonian symptoms as an initial manifestation in a Japanese patient with
acquired immunodeficiency syndrome and Toxoplasma infection. Intern Med
39: 1111–1114.
194. Koseoglu E, Yazar S, Koc I (2009) Is Toxoplasma gondii a causal agent in
migraine? Am J Med Sci 338: 120–122.
195. Prandota J (2010) Migraine associated with patent foramen ovale may be
caused by reactivation of cerebral toxoplasmosis triggered by arterial blood
oxygen desaturation. Int J Neurosci 120: 81–87.
196. Prandota J (2009) The importance of Toxoplasma gondii infection in diseases
presenting wit h headaches. Headaches and asept ic meningitis may be
manifestations of the Jarisch-Herxheimer reaction. Int J Neurosci 119: 2144–
2182.
197. Prandota J (2007) Recurrent headache as the main symptom of acquired
cerebral toxoplasmosis in nonhuman immunodeficiency virus-infected subjects
with no lymphadenopathy: the parasite may be responsible for the neurogenic
inflammation postulated as a cause of different types of headaches. Am J Ther
14: 63–105.
198. Kusbeci OY, Miman O, Yaman M, Aktepe OC, Yazar S (2011) Could
Toxoplasma gondii have any role in Alzheimer disease? Alzheimer Dis Assoc
Disord 25: 1–3.
199. Prandota J (2009) Mollaret meningitis may be caused by reactivation of latent
cerebral toxoplasmosis. Int J Neurosci 119: 1655–1692.
200. Palmer BS (2007) Meta-analysis of three case controlled studies and an
ecological study into the link between cryptogenic epilepsy and chronic
toxoplasmosis infection. Seizure 16: 657–663.
201. Stommel EW, Seguin R, Thadani VM, Schwartzman JD, Gilbert K, et al.
(2001) Cryptogenic epilepsy: an infectious etiology? Epilepsia 42: 436–438.
202. Michaoowicz R, Jozwiak S, Ignatowicz R, Szwabowska-Orzeszko E (1988)
Landau-Kleffner syndrome—epileptic aphasia in children—possible role of
Toxoplasma gondii infection. Acta Paediatr Hung 29: 337–342.
203. Riga M, Kefalidis G, Chatzimoschou A, Tripsianis G, Kartali S, et al. (2011)
Increased seroprevalence of Toxoplasma gondii in a population of patients with
Bell’s palsy: a sceptical interpretation of the results regarding the pathogenesis
of facial nerve palsy. Eur Arch Otorhinolaryngol 268: 1087–1092.
204. Andrade GM, Resende LM, Goulart EM, Siqueira AL, Vitor RW, et al. (2008)
Hearing loss in congenital toxoplasmosis detected by newborn screening.
Braz J Otorhinolaryngol 74: 21–28.
205. al Muhaimeed H (1996) Prevalence of sensorineural hearing loss due to
toxoplasmosis in Saudi children: a hospital based study. Int J Pediat r
Otorhinolaryngol 34: 1–8.
206. Yamakawa R, Yamashita Y, Yano A, Morita J, Kato H (1996) Congenital
toxoplasmosis complicated by central diabetes insipidus in an infant with Down
syndrome. Brain Dev 18: 75–77.
207. Oygur N, Yilmaz G, Ozkaynak C, Guven AG (1998) Central diabetes insipitus
in a patient with congenital toxoplasmosis. Am J Perinatol 15: 191–192.
208. Nitta A, Suzumura H, Kano K, Arisaka O (2 006) Congenital toxoplasmosis
complicated with central diabetes insipidus in the first week of life. J Pediatr
148: 283.
209. Gherardi R, Baudrimont M, Lionnet F, Salord JM, Duvivier C, et al. (1992)
Skeletal muscle toxoplasmosis in patients with acquired immunodeficiency
syndrome: a clinical and pathological study. Ann Neurol 32: 535–542.
210. Massa G, Vanderschueren-Lodeweyckx M, Van Vliet G, Craen M, de Zegher
F, et al. (1989) Hypothalamo-pituitary dysfunction in congenital toxoplasmosis.
Eur J Pediatr 148: 742–744.
211. Siahanidou T, Tsoumas D, Kanaka-G antenbein C, Mandyla H (2006)
Neuroendocrine abnormalities in a neonate with congenital toxoplasmosis.
J Pediatr Endocrinol Metab 19: 1363–1366.
212. Wrensch M, Bondy ML, Wiencke J, Yost M (1993) Environmental risk factors
for primary malignant brain tumors: a review. J Neurooncol 17: 47–64.
213. Ryan P, Hurley SF, Johnson AM, Salzberg M, Lee MW, et al. (1993) Tumours
of the brain and presence of antibodies to Toxoplasma gondii. Int J Immunol 22:
412–419.
214. Thomas F, Lafferty KD, Brodeur J, Elguero E, Gauthier-Clerc M, et al. (2012)
Incidence of adult brain cancers is higher in countries where the protozoan
parasite Toxoplasma gondii is common. Biol Lett 8: 101–103.
215. Vittecoq M, Elguero E, Lafferty KD, Roche B, Brodeu r J, et al. (2012) Brain
cancer mortality rates increase with Toxoplasma gondii seroprevalence in France.
Infect Genet Evol 12: 496–498.
216. Johnson MD, Jennings MT, Gold LI, Moses HL (1993) Transforming growth
factor-beta in neural embryogenesis and neoplasia. Hum Pathol 24: 457–462.
217. Ortiz-Munoz AB, Cuadrado-Mendez L, Sanchis-Belenguer R (1984) [Possible
interactions between Toxoplasma gondii infection and the presence of non-
Hodgkin’s lymphoma]. Rev Esp Oncol 31: 237–245.
218. Herold MA, Kuhne R, Vosberg M, Ostheeren-Michaelis S, Vogt P, et al.
(2009) Disseminated toxoplasmosis in a patient with non-Hodgkin lymphoma.
Infection 37: 551–554.
219. Yazar S, Yaman O, Eser B, Altuntas F, Kurnaz F, et al. (2004) Investigation of
anti-Toxoplasma gondii antibodies in patients with neoplasia. J Med Microbiol 53:
1183–1186.
220. Alibek K, Kakpenova A, Baiken Y (2013) Role of infectious agents in the
carcinogenesis of brain and head and neck cancers. Infect Agent Cancer 8: 7.
221. Grudzien M (1968) [Toxoplasma reactions in women with neoplasms]. Pol Tyg
Lek 23: 54–56.
222. Gupta A, Driscoll MS (2010) Do hormones influence melanoma? Facts and
controversies. Clin Dermatol 28: 287–292.
223. Nguyen Huu S, Oster M, Avril MF, Boitier F, Mortier L, et al. (2009) Fetal
microchimeric cells participate in tumour angiogenesis in melanomas occurring
during pregnancy. Am J Pathol 174: 630–637.
224. Kim DS, Park SH, Park KC (2004) Transforming growth factor-beta1
decreases melanin synthesis via delayed extracellular signal-regulated kinase
activation. Int J Biochem Cell Biol 36: 1482–1491.
225. Nagineni CN, Detrick B, Hooks JJ (2002) Transforming growth factor-bet a
expression in human retinal pigment epithelial cells is enhanced by Toxoplasma
gondii: a possible role in the immunopathogenesis of retinochoroiditis. Clin Exp
Immunol 128: 372–378.
226. Connor TB, Jr., Roberts AB, Sporn MB, Danielpour D, Dart LL, et al. (1989)
Correlation of fibrosis and transforming growth factor-beta type 2 levels in the
eye. J Clin Invest 83: 1661–1666.
227. Vos GH (1987) Population studies showing cross-reactivity of Toxoplasm a gondii
antibodies with antibodies to malignant cervical tissue antigens. S Afr Med J 71:
78–82.
228. Sanchis-Belenguer R, Cuadrado-Mendez L, Ortiz Munoz AB (1984) [Possible
interactions between Toxoplasma gondii infection and the presence of carcinomas
of female genitalia and the breast]. Rev Esp Oncol 31: 247–255.
229. Yazar S, Gur M, Ozdogru I, Yaman O, Oguzhan A, et al. (2006) Anti-
Toxoplasma gondii antibodies in patients with chronic heart failure. J Med
Microbiol 55: 89–92.
230. Lappin MR (2010) Update on the diagnosis and management of Toxoplasma
gondii infection in cats. Top Companion Anim Med 25: 136–141.
231. Paspalaki PK, Mihailidou EP, Bitsori M, Tsagkara ki D, Mantzouranis E (2001)
Polyomyositis and myocarditis associated with acquired toxoplasmosis in an
immunocompetent girl. BMC Musculoskelet Disord 2: 8.
232. Prandota J (2012) Gastrointestinal tract abnormalities in autism, inflammatory
bowel disease and many other clinical entities may be due to T. gondii infection.
Open Acc Sci Rep 1: 256.
233. Arciszewski M, Pierzynowski S, Ekblad E (2005) Lipopolysaccharide induces
cell death in cultured porcine myenteric neurons. Dig Dis Sci 50: 1661–1668.
234. Lidar M, Langevitz P, Barzilai O, Ram M, Porat-Katz BS, et al. (200 9)
Infectious serologies and autoan tibodies in inflammatory bowel disease:
insinuations at a true pathogenic role. Ann N Y Acad Sci 1173: 640–648.
235. Rostami Nejad M, Rostami K, Cheraghipour K, Nazemalhosseini Mojarad E,
Volta U, et al. (2011) Celiac disease increases the risk of Toxoplasma gondii
infection in a large cohort of pregnant women. Am J Gastroenterol 106: 548–
549.
236. Alvarado-Esquivel C, Estrada-Martinez S (2011) Toxoplasma gondii infectio n and
abdominal hernia: evidence of a new association. Parasit Vectors 4: 112.
237. Bars L, Hecht Y, Callard P, Ferrier JP (1978) [Hepatitis due to acquired
toxoplasmosis. Case report and review of the literature]. Med Chir Dig 7: 485–
486.
238. Weitberg AB, Alper JC, Diamond I, Fligiel Z (1979) Acute granulomatous
hepatitis in the course of acquired toxoplasmosis. N Engl J Med 300: 1093–
1096.
239. Frenkel JK, Remington JS (1980) Hepatitis in toxoplasmosis. N Engl J Med
302: 178–179.
240. Roca B, Calabuig C, Arenas M (1992) [Toxoplasmosis and hepatitis]. Med
Clin (Barc) 99: 595–596.
241. Vethanyagam A, Bryceson AD (1976) Acquired toxoplasmosis presenting as
hepatitis. Trans R Soc Trop Med Hyg 70: 524–525.
242. Lampon N, Hermida-Cadahia EF, Riveiro A, Tutor JC (2012) Association
between butyrylcholinesterase activity and low-grade systemic inflammation.
Ann Hepatol 11: 356–363.
243. Das UN (2007) Acetylcholinesterase and butyrylcholinesterase as possible
markers of low-grade systemic inflammation. Med Sci Monit 13: RA214–221.
Correlation of Toxoplasmosis with Disease Burden
PLOS ONE | www.plosone.org 19 March 2014 | Volume 9 | Issue 3 | e90203
244. Das UN (2012) Acetylcholinesterase and butyrylcholinesterase as markers of
low-grade systemic inflammation. Ann Hepatol 11: 409–411.
245. Agmon-Levin N, Ram M, Barzilai O, Porat-Katz BS, Parikman R, et al. (2009)
Prevalence of hepatitis C serum antibody in autoimmune diseases.
J Autoimmun 32: 261–266.
246. Pavlov VA (2008) Cholinergic modulation of inflammation. Int J Clin Exp Med
1: 203–212.
247. Bertoli F, Espino M, Arosemena JR, Fishback JL, Frenkel JK (1995) A
spectrum in the pa thology of toxo plasmosis in pa tients with acq uired
immunodeficiency syndrome. Arch Pathol Lab Med 119: 214–224.
248. Coash M, Forouhar F, Wu CH, Wu GY (2012) Granulomatous liver diseases: a
review. J Formos Med Assoc 111: 3–13.
249. Ustun S, Aksoy U, Dagci H, Ersoz G (2004) Incidence of toxoplasmosi s in
patients with cirrhosis. World J Gastroenterol 10: 452–454.
250. Bermudez LE, Covaro G, Remington J (1993) Infection of murine
macrophages with Toxoplasma gondii is associated with release of transforming
growth factor beta and downregulation of expression of tumor necrosis factor
receptors. Infect Immun 61: 4126–4130.
251. Seabra SH, de Souza W, Damatta RA (2004) Toxoplasma gondii exposes
phosphatidylserine inducing a TGF-beta1 autocrine effect orchestrating
macrophage evasion. Biochem Biophys Res Commun 324: 744–752.
252. Borthwick LA, Wynn TA, Fisher AJ (2013) Cytokine mediated tissue fibrosis.
Biochim Biophys Acta 1832: 1049–1060.
253. Da Silva AS, Tonin AA, Thorstenberg ML, Leal DB, Fighera R, et al. (2013)
Relationship between butyrylcholinesterase activity and liver injury in mice
acute infected with Toxoplasma gondii. Pathol Res Pract 209: 95–98.
254. Shapira Y, Agmon-Levin N, Renaudineau Y, Porat-Katz BS, Barzilai O, et al.
(2012) Serum markers of infections in patients with primary biliary cirrhosis:
evidence of infection burden. Exp Mol Pathol 93: 386–390.
255. Haskell L, Fusco MJ, Ares L, Sublay B (1989) Disseminated toxoplasmosis
presenting as symptomatic orchitis and nephrotic syndrome. Am J Med Sci
298: 185–190.
256. Fitzgerald JF (1988) Cholestatic disorders of infancy. Pediatr Clin North Am
35: 357–373.
257. Glassman MS, Dellalzedah S, Beneck D, Seashore JH (1991) Coincidence of
congenital toxoplasmosis and biliary atresia in an infant. J Pediatr Gastro-
enterol Nutr 13: 298–300.
258. de Oliveira Fdos S, Kieling CO, dos Santos JL, de Leon Lima PP, Vieira S, et
al. (2010) Serum and tissue transforming [corrected] growth factor beta1 in
children with biliary atresia. J Pediatr Surg 45: 1784–1790.
259. Al-Masri AN, Flemming P, Rodeck B, Melter M, Leonhardt J, et al. (2006)
Expression of the interferon-induced Mx proteins in biliary atresia. J Pediatr
Surg 41: 1139–1143.
260. Hayashida M, Nishimoto Y, Matsuura T, Tak ahashi Y, Kohashi K, et al.
(2007) The evidence of maternal microchimerism in biliary atresia using
fluorescent in situ hybridization. J Pediatr Surg 42: 2097–2101.
261. MacSween RN, Galbraith I, Thomas MA, Watkinson G, Ludlam GB (1973)
Phytohaemagglutinin (PHA) induced lymphocyte transformation and Toxoplas-
ma gondii antibody studies in primary biliary cirrhosis. Evidence of impaired
cell-mediated immunity. Clin Exp Immunol 15: 35–42.
262. Prandota J (2013) T. gondii infection acquired during pregnancy and/or after
birth may be responsible for development of both type 1 and 2 diabetes
mellitus. J Diabetes Metab 4: 55.
263. Gokce C, Yazar S, Bayram F, Gundogan K, Yaman O, et al. (2008) Anti-
Toxoplasma gondii antibodies in type 2 diabetes. Natl Med J India 21: 51–51.
264. Krause I, Anaya JM, Fraser A, Barzilai O, Ram M, et al. (2009) Anti-infectious
antibodies and autoimmune-associated autoantibodies in patients with type I
diabetes mellitus and their close family members. Ann N Y Acad Sci 1173:
633–639.
265. Slosarkova S, Literak I, Skrivanek M, Svobodova V, Suchy P, et al. (1999)
Toxoplasmosis and iodine deficiency in Angora goats. Vet Parasitol 81: 89–97.
266. Vasquez-Garibay EM, Romero-Velarde E (2009) Iodine deficiency in relation
to iron deficiency and parasitosis: Effect of iron status and parasites on iodine
deficiency disorders. Comprehensive Handbook of Iodine Nutritional,
Biochemical, Pathological and Therapeutic Aspects: 499–511.
267. Singh S, Singh N, Pandav R, Pandav CS, Karmarkar MG (1994) Toxoplasma
gondii infection & its association with iodine deficiency in a residential school in
a tribal area of Maharashtra. Indian J Med Res 99: 27–31.
268. Marani L, Venturi S (1986) [Iodine and delayed immunity]. Minerva Med 77:
805–809.
269. Tozzoli R, Barzilai O, Ram M, Villalta D, Bizzaro N, et al. (2008) Infections
and autoimmune thyroid diseases: parallel detection of antibodies against
pathogens with proteomic technology. Autoimmun Rev 8: 112–115.
270. Galofre JC (2012) Microchimerism in graves’ disease. J Thyroid Res 2012:
724382.
271. Renne C, Ramos Lopez E, Steimle-Grauer SA, Ziolkowski P, Pani MA, et al.
(2004) Thyroid fetal male microchimerisms in mothers with thyroid disorders:
presence of Y-chromosomal immunofluorescence in thyroid-infiltrating lym-
phocytes is more prevalent in Hashimoto’s thyroiditis and Graves’ disease than
in follicular adenomas. J Clin Endocrinol Metab 89: 5810–5814.
272. Tomairek HA, Saeid MS, Morsy TA, Michael SA (1982) Toxoplasma gondii as a
cause of rheumatoid arthritis. J Egypt Soc Parasitol 12: 17–23.
273. Mousa MA, Soliman HE, el Shafie MS, Abdel-Baky MS, Aly MM (1988)
Toxoplasma seropositivity in patients with rheumatoid arthritis. J Egypt Soc
Parasitol 18: 345–351.
274. Torrey EF, Yolken RH (2001) The schizophrenia-rheumatoid arthritis
connection: infectious, immune, or both? Brain Behav Immun 15: 401–410.
275. Balleari E, Cutolo M, Accardo S (1991) Adult-onset Still’s disease associated to
Toxoplasma gondii infection. Clin Rheumatol 10: 326–327.
276. Chan WF, Atkins CJ, Naysmith D, van der Westhuizen N, Woo J, et al. (2012)
Microchimerism in the rheumatoid nodules of patients with rheumatoid
arthritis. Arthritis Rheum 64: 380–388.
277. Shapira Y, Agmon-Levin N, Selmi C, Petrikova J, Barzilai O, et al. (201 2)
Prevalence of anti-Toxoplasma antibodies in patients with autoimmune diseases.
J Autoimmun 39: 112–116.
278. Behan WM, Behan PO, Draper IT, Williams H (1983) Does Toxoplasma cause
polymyositis? Report of a case of polymyositis associated with toxoplasmosis
and a critical review of the literature. Acta Neuropathol (Berl) 61: 246–252.
279. Hassene A, Vital A, Anghel A, Guez S, Series C (2008) Acute acquired
toxoplasmosis presenting as polymyositis and chorioretinitis in immunocom-
petent patient. Joint Bone Spine 75: 603–605.
280. Gomes AF, Guimaraes EV, Carvalho L, Correa JR, Mendonca-Lima L, et al.
(2011) Toxoplasma gondii down modulates cadherin expression in skeletal muscle
cells inhibiting myogenesis. BMC Microbiol 11: 110.
281. Cuturic M, Hayat GR, Vogler CA, Velasques A (1997) Toxoplasmic
polymyositis revisited: case report and review of literature. Neuromuscul
Disord 7: 390–396.
282. Karasawa T, Takizawa I, Morita K, Ishibashi H, Kanayama S, et al. (1981)
Polymyositis and toxoplasmosis. Acta Pathol Jpn 31: 675–680.
283. Cuomo G, D’Abrosca V, Rizzo V, Nardiello S, La Montagna G, et al. (2013)
Severe polymyositis due to Toxoplasma gondii in an adult immunocompetent
patient: a case report and review of the literature. Infection 41: 859–862.
284. Arnson Y, Amital H, Guiducci S, Matucci-Cerinic M, Valentini G, et al. (2009)
The role of infections in the immunopathogensis of systemic sclerosis—
evidence from serological studies. Ann N Y Acad Sci 1173: 627–632.
285. Arieli G, Arieli S, Feuerman EJ (1979) [Toxoplasma infection in scleroderma].
Harefuah 96: 338.
286. Wilcox MH, Powell RJ, Pugh SF, Balfour AH (1990) Toxoplasmosis and
systemic lupus erythematosus. Ann Rheum Dis 49: 254–257.
287. Lidar M, Lipschitz N, Langevitz P, Barzilai O, Ram M, et al. (2009) Infectious
serologies and autoantibodies in Wegener’s granulomatosis and other
vasculitides: novel associations disclosed using the Rad BioPlex 2200.
Ann N Y Acad Sci 1173: 649–657.
288. Smith JR, Cunningham ET Jr. (2002) Atypical presentations of ocular
toxoplasmosis. Curr Opin Ophthalmol 13: 387–392.
289. Suhardjo, Utomo PT, Agni AN (2003) Clinical manifestations of ocular
toxoplasmosis in Yogyakarta, Indonesia: a clinical review of 173 cases.
Southeast Asian J Trop Med Public Health 34: 291–297.
290. Pleyer U, Torun N, Liesenfeld O (2007) [Ocular toxoplasm osis]. Ophthalmo-
loge 104: 603–615, quiz 616.
291. Soares JA, Carvalho SF, Caldeira AP (2012) Profile of pregnant women and
children treated at a reference center for congenital toxoplasmosis in the
northern state of Minas Gerais, Brazil. Rev Soc Bras Med Trop 45: 55–59.
292. Sheets CW, Grewal DS, Greenfield DS (2009) Ocular toxoplasmosis presenting
with focal retinal nerve fiber atrophy simulating glaucoma. J Glaucoma 18:
129–131.
293. Orefice JL, Costa RA, Orefice F, Campos W, da Costa-Lima D, Jr., et al.
(2007) Vitreoretinal morphology in active ocular toxoplasmosis: a prospective
study by optical coherence tomography. Br J Ophthalmol 91: 773–780.
294. Stahl W, Dias JA, Turek G, Kaneda Y (1995) Etiology of ovarian dysfunction
in chronic murine toxoplasmosis. Parasitol Res 81: 114–120.
295. Furtado GC, Cao Y, Joiner KA (1992) Laminin on Toxop lasma gondii mediates
parasite binding to the beta 1 integrin receptor alpha 6 beta 1 on human
foreskin fibroblasts and Chinese hamster ovary cells. Infect Immun 60: 4925–
4931.
296. Abdoli A, Dalimi A, Movahedin M (2012) Impaired reproductive function of
male rats infected with Toxoplasma gondii. Andrologia 44: 679–687.
297. Stahl W, Kaneda Y, Tanabe M, Kumar SA (1995) Uterine atrophy in chronic
murine toxoplasmosis due to ovarian dysfunction. Parasitol Res 81: 109–113.
298. Terpsidis KI, Papazahariadou MG, Taitzoglou IA, Papaioannou NG,
Georgiadis MP, et al. (2009) Toxoplasma gondii: reproductive parameters in
experimentally infected male rats. Exp Parasitol 121: 238–241.
299. Lopes WD, da Costa AJ, Santana LF, Dos Santos RS, Rossanese WM, et al.
(2009) Aspects of Toxoplasma infection on the reproductive system of
experimentally infected rams (ovis aries). J Parasitol Res 2009: Article ID
602803, 6 pages.
300. Lopes WDZ, Santos TR, Luvizotto MCR, Sakamoto CAM, Oliveira GP, et al.
(2011) Histopathology of the reproductive system of male sheep experimentally
infected with Toxoplasma gondii. Parasitol Res 109: 405–409.
301. Toporovski J, Romano S, Hartmann S, Benini W, Chieffi PP (2012) Nephrotic
syndrome associated with toxoplasmosis. Report of seven cases Rev Inst Med
Trop Sao Paulo 54: 61–64.
302. Oseroff A (1988) Toxoplasmosis associated with nephrotic syndrome in an
adult. South Med J 81, 95–96.
303. Shahin B, Papadopoulou ZL, Jenis EH (1974) Congenital nephrotic syndrome
associated with congenital toxoplasmosis. J Pediatr 85: 366–370.
Correlation of Toxoplasmosis with Disease Burden
PLOS ONE | www.plosone.org 20 March 2014 | Volume 9 | Issue 3 | e90203
304. Massiere JP, Delafaye C, Le Guen E, Condat D (1989) [Acquired
toxoplasmosis associated with nephrotic syndrome in an adult]. Presse Med
18: 1393.
305. Wickbom B, Winberg J (1972) Coincidence of conge nital toxoplasmosis and
acute nephritis with nephrotic syndrome. Acta Paediatr Scand 61: 470–472.
306. Beale MG, Strayer DS, Kissane JM, Robson AM (1979) Congenital
glomerulosclerosis and nephrotic syndrome in two infants. Speculations and
pathogenesis. Am J Dis Child 133: 842–845.
307. Pawlowska-Kamieniak A, Mroczkowska-Juchkiewicz A, Papierkowsk i A (1998)
[Henoch-Schoenlein purpura and toxocarosis]. Pol Merkur Lekarski 4: 217–
218.
308. Hamidou MA, Gueglio B, Cassagneau E, Trewick D, Grolleau JY (1999)
Henoch-Schonlein purpura associated with Toxocara canis infection.
J Rheumatol 26: 443–445.
309. Lam C, Imundo L, Hirsch D, Yu Z, D’Agati V (1999) Glomerulonephritis in a
neonate with atypical congenital lupus and toxoplasmosis. Pediatr Nephrol 13:
850–853.
310. Van Velthuysen ML (1996) Glomerulopathy associated with parasitic
infections. Parasitol Today 12: 102–107.
311. van Velthuysen ML, Florquin S (2000) Glomerulopathy associated with
parasitic infections. Clin Microbiol Rev 13: 55–66.
312. Kapoor S (2012) The close relationship between toxoplasmosis and kidney
function Rev Inst Med Trop Sao Paulo 54: 318–318.
313. Milovanovic I, Vujanic M, Klun I, Bobic B, Nikolic A, et al. (2009) Toxoplasma
gondii infection induces lipid metabolism alterations in the murine host. Mem
Inst Oswaldo Cruz 104: 175–178.
314. Coppens I (2006) Contribution of host lipids to Toxoplasma pathogenesis. Cell
Microbiol 8: 1–9.
315. Coppens I, Sinai AP, Joiner KA (2000) Toxoplasma gondii exploits host low-
density lipoprotein receptor-mediated endocytosis for cholesterol acquisition.
J Cell Biol 149: 167–180.
316. Charron AJ, Sibley LD (2002) Host cells: mobilizable lipid resources for the
intracellular parasite Toxoplasma gondii. J Cell Sci 115: 3049–3059.
317. Sehgal A, Bettiol S, Pypaert M, Wenk MR, Kaasch A, et al. (2005) Peculiarities
of host cholesterol transport to the unique intracellular vacuole containing
Toxoplasma. Traffic 6: 1125–1141.
318. Calderon-Margalit R, Adler B, Abramson JH, Gofin J, Kark JD (2006)
Butyrylcholinesterase activity, cardiovascular risk factors, and mortality in
middle-aged and elderly men and women in Jerusalem. Clin Chem 52: 845–
852.
319. Webster JP, Lamberton PHL, Donnelly CA, Torrey EF (2006) Parasites as
causative agents of human affective disorders? The impact of anti-psychotic,
mood-stabilizer and anti-parasite medication on Toxoplasma gondii ’s ability to
alter host behaviour. Proc R Soc Biol Sci Ser B 273: 1023–1030.
320. Berdoy M, Webster JP, Macdonald DW (2000) Fatal attraction in rats infected
with Toxoplasma gondii. Proc R Soc Biol Sci Ser B 267: 1591–1594.
321. Flegr J, Kodym P, Tolarova´ V (2000) Correlation of duration of latent
Toxoplasma gondii infection with personality changes in women. Biol Psychol 53:
57–68.
322. Dama MS (2012) Parasite stress predicts offspring sex ratio. PLoS ONE 7.
323. WHO (2008) The Global Burden of Disease: 2004 update. Geneva : World
Health Organization.
324. Lopez AD (2006) Global burden of disease and risk factors. New York, NY,
Washington, DC: Oxford University Press, World Bank. 475 p.
325. Barber N (2004) Sex ratio at birth, polygyny, and fertility: a cross-national
study. Soc Biol 51: 71–77.
326. Siegel S, Castellan NJ (1988) Nonparametric statistics for the behavioral
sciences. New York: McGraw-Hill. xxiii, 399 p.
327. Kan
ˇkova´S
ˇ, Kodym P, Flegr J (2011) Direct evidence of Toxoplasma-induced
changes in serum testosterone in mice. Exp Parasitol 128: 181–183.
328. Tabachnick BG, Fidell LS (2007 ) Using multivariate statistics. Boston:
Pearson/Allyn & Bacon. xxviii, 980 p. p.
329. Thompson B (2006) Foundations of behavioral statistics: an insight-based
approach. New York: Guilford Press. xii, 457 p. p.
330. Fond G, Capdevielle D, Macgregor A, Attal J, Larue A, et al. (2013) Toxoplasma
gondii: a potential role in the genesis of psychiatric disorders. Encephale 39: 38–
43.
331. Flegr J (2013) How and why Toxoplasma makes us crazy. Trends Parasitol 29:
156–163.
332. Vyas A (2013) Parasite-augmented mate choice and reduction in innate fear in
rats infected by Toxoplasma gondii. J Exp Biol 216: 120–126.
333. Hostomska
´L,Jı
´rovec O, Hora´c
ˇkova´ M, Hrubcova´ M (1957) The role of
toxoplasmosis in the mother in the development of mongolism in the child (in
Czech). C
ˇeskosl Pediatr 12: 713–723.
334. Dimier IH, Bout DT (1998) Interferon-gamma-activated primary enterocytes
inhibit Toxoplasma gondii replication: a role for intracellular iron. Immunology
94: 488–495.
335. Slosarkova S, Literak I, Skrivanek M, Svobodova V, Suchy P, et al. (1999)
Toxoplasmosis and iodine deficiency in Angora goats. Vet Parasitol 81: 89–97.
336. Kan
ˇkova´S
ˇ,S
ˇulc J, Nouzova´ K, Fajfrlik K, Frynta D, et al. (2007) Women
infected with parasite Toxoplasma have more sons. Naturwissenschaften 94:
122–127.
337. Kan
ˇkova S, S
ˇulc J, Kr
ˇivohlava´ R, Kube
ˇna A, Flegr J (2012) Slower postnatal
motor development in infants of mothers with latent toxoplasmosis during the
first 18 months of life. Early Hum Dev 88: 879–884.
338. Kan
ˇkova´S
ˇ, Kodym P, Frynta D, Vavr
ˇinova´ R, Kube
ˇna A, et al. (2007)
Influence of latent to xoplasmosis on the se condary sex ratio in m ice.
Parasitology 134: 1709–1717.
339. Prandota J (2012) Rhesus-associated glycoprotein (RhAG) phenotype of the red
blood cells modulates T. gondii infection-associated psychomotor performance
reaction times and changes in the human personality profile. Impaired function
of the CO
2
, AQP1, and AQP4 gas channels may cause hypoxia and thus
enhance neuroinflammation in autistic individuals. In: Gemma C, editor.
Neuroinflammation: Pathogenesis, Mechanisms and Management. New York:
Nova Publishers. pp. 423–439.
340. Patja A, Davidkin I, Kurki T, Kallio MJT, Valle M, et al. (2000) Serious
adverse events after measles-mumps-rubella vaccination during a fourteen-year
prospective follow-up. Pediatr Infect Dis J 19: 1127–1134.
341. Packard KA, Khan MM (2003) Effects of histamine on Th1/Th2 cytokine
balance. Int Immunopharmacol 3: 909–920.
342. Yazar S, Arman F, Yalcin S, Dimirtas F, Yaman O, et al. (2003) Investigation
of probable relationship between Toxoplasma gondii and cryptogenic epilepsy.
Seiz Europ J Epil 12: 107–109.
343. Critchley EM, Vakil SD, Hutchinson DN, Taylor P (1982) Toxoplasma,Toxocara,
and epilepsy. Epilepsia 23: 315–321.
344. Fuks JM, Arrighi RB, Weidner JM, Kumar Mendu S, Jin Z, et al. (2012)
GABAergic signaling is linked to a hypermigratory phenotype in dendritic cells
infected by Toxoplasma gondii. PLoS Pathog 8: e1003051.
345. Hwang IY, Quan JH, Ahn MH, Ahmed HAH, Cha GH, et al. (2010)
Toxoplasma gondii infection inhibits the mitocho ndrial apoptosis through
induction of Bcl-2 and HSP70. Parasitol Res 107: 1313–1321.
346. Hippe D, Weber A, Zhou LY, Chang DC, Hacker G, et al. (2009) Toxoplasma
gondii infection confers resistance against Bim(S)-induced apoptosis by
preventing the activation and mitochondrial targeting of pro-apoptotic Bax.
J Cell Sci 122: 3511–3521.
347. Hippe D, Lytovchenko O, Schmitz I, Luder CGK (2008) Fas/CD 95-mediated
apoptosis of type II cells is blocked by Toxoplasma gondii primarily via
interference with the mitochondrial amplification loop. Infect Immun 76:
2905–2912.
348. Kim JY, Ahn MH, Jun HS, Jung JW, Ryu JS, et al. (2006) Toxoplasma gondii
inhibits apoptosis in infected cells by caspase inactivation and NF-kappa B
activation. Yonsei Med J 47: 862–869.
349. Hippe D, Vutova P, Hacker G, Gross U, Luder CGK (2006) Toxoplasma gondii
inhibits host cell apoptosis triggered by both intrinsic and extrinsic proapoptotic
signals. Int J Med Microbiol 296: 105-106.
350. Lim A, Kumar V, Hari Dass SA, Vyas A (2013) Toxoplasma gondii infection
enhances testicular steroidogenesis in rats. Mol Ecol 22: 102–110.
351. Flegr J, Lindova´ J, Pivon
ˇkova´ V, Havlı
´c
ˇek J (2008) Brief Communication: latent
toxoplasmosis and salivary testosterone concentration-important confounding
factors in second to fourth digit ratio studies. Am J Phys Anthropol 137: 479–
484.
352. Flegr J, Lindova´ J, Kodym P (2008) Sex-dependent toxoplasmosis-associated
differences in testosterone concentration in humans. Parasitology 135: 427–
431.
353. Hollander E, Stein DJ, Kwon JH, Rowland C, Wong CM, et al. (1998)
Psychosocial function and economic costs of obsessive–compulsive disorder.
CNS Spectrum 3: 48–50 suppl.
354. Torres AR, Prince MJ, Bebbington PE, Bhugra D, Brugha TS, et al. (2006)
Obsessive-compulsive disorder: Prevalence, comorbidity, impact, and help-
seeking in the British Na tional Psychiatr ic Morbidity Surve y of 2000.
Am J Psychiatry 163: 1978–1985.
355. Kamath P, Reddy YC, Kandavel T (2007) Suicidal behavior in obsessive-
compulsive disorder. J Clin Psychiatry 68: 1741–1750.
356. Diaconu G, Turecki G (2009) Obsessive-compulsive personality disorder and
suicidal behavior: evidence for a positive association in a sample of depressed
patients. J Clin Psychiatry 70: 1551–1556.
357. Wasserman EE, Nelson K, Rose NR, Rhode C, Pillion JP, et al. (2009)
Infection and thyroid autoimmunity: A seroepidemiologic study of TPOaAb.
Autoimmunity 42: 439–446.
358. Berlin T, Zandman-Goddard G, Blank M, Matthias T, Pfeiffer S, et al. (2007)
Autoantibodies in nonautoimmune individuals during infections. Ann N Y Acad
Sci 1108: 584–593.
359. Appenzeller S, Shoenfeld Y, de Carvalho JF (2012) Neurologic manifestations
of autoimmune diseases. Autoimmune Dis 2012: 683212.
360. Fugazzola L, Cirello V, Beck-Peccoz P (2011) Fetal microchimerism as an
explanation of disease. Nat Rev Endocrinol 7: 89–97.
361. Prandota J (2012) Increased generation of antibodies and autoantibodies
directed against brain proteins in patients with autism and their families may be
caused by T. gondii infection. Maternal and fetal microchimerisms probably
play an important role in these processes acting as a ‘‘Trojan horse’’ in
dissemination of the parasite. In: Gemma C, editor. Neuroinflammation
Pathogenesis, Mechanisms, and Management. New York: Nova Publishers. pp.
447–638.
362. Wilson GS (1967) Indirect effects: provocation disease. The Hazards of
Immunization. London, England: The Athlone Press. pp. 265–280.
Correlation of Toxoplasmosis with Disease Burden
PLOS ONE | www.plosone.org 21 March 2014 | Volume 9 | Issue 3 | e90203
363. Prandota J (2004) Urinary tract diseases revealed after DTP vaccination in
infants and young children. Cytokine irregularities and down-regulation of
cytochrome P-450 enzymes induced by the vaccine may uncover latent diseases
in genetically predisposed subjects. Am J Ther 11: 344–353.
364. Ansher SS, Thompson W (1994) Modulation of hepatic mRNA levels after
administration of lipopolysaccharide and diphtheria and tetanus toxoids and
pertussis vaccine adsorbed (DTP vaccine) to mice. Hepatology 20: 984–991.
365. Fantuzzi G, Sironi M, Delgado R, Cantoni L, Rizzardini M, et al. (1994)
Depression of liver metabolism and induction of cytokine release by diphtheria
and tetanus toxoids and pertussis vaccines: role of Bordetella pertussis cells in
toxicity. Infect Immun 62: 29–32.
366. King MD, Lindsay DS, Holladay S, Ehrich M (2003) Neurotoxicity and
immunotoxicity assessment in CBA/J mice with chronic Toxoplasma gondii
infection and single-dose exposure to methylmercury. Int J Toxicol 22: 53–61.
367. Pappas G, Roussos N, Falagas ME (2009) Toxoplasmosis snapshots: Global
status of Toxoplasma gondii seroprevalence and implications for pregnancy and
congenital toxoplasmosis. Int J Parasitol 39: 1385–1394.
368. Prandota J (2004) Possible pathomechanisms of sudden infant death syndrome:
key role of chronic hypoxia, infection/inflammation states, cytokine irregular-
ities, and metabolic trauma in genetically predisposed infants. Am J Ther 11:
517–546.
369. McMartin KI, Platt MS, Hackman R, Klein J, Smialek JE, et al. (2002) Lung
tissue concentrations of nicotine in sudden infant death syndrome (SIDS).
J Pediatr 140: 205–209.
370. Milerad J, Vege A, Opdal SH, Rognum TO (1998) Objective measurements of
nicotine exposure in victims of sudden infant death syndrome and in other
unexpected child deaths. J Pediatr 133: 232–236.
371. Arling TA, Yolken RH, Lapidus M, Langenberg P, Dickerson FB, et al. (2009)
Toxoplasma gondii antibody titers and history of suicide attempts in patients with
recurrent mood disorders. J Nerv Ment Dis 197: 905–908.
372. Flegr J, Klose J, Novotna´ M, Berenreitterova´ M, Havlı
´c
ˇek J (2009) Increased
incidence of traffic accidents in Toxoplasma-infected military drivers and
protective effect RhD molecule revealed by a large-scale prospective cohort
study. BMC Infect Dis 9: art. 72.
373. Novotna´ M, Havlı
´c
ˇek J, Smith AP, Kolbekova´ P, Skallova´ A, et al. (2008)
Toxoplasma and reaction time: Role of toxoplasmosis in the origin, preservation
and geographical distribution of Rh blood group polymorphism. Parasitology
135: 1253–1261.
374. Flegr J, Novotna´ M, Lindova´ J, Havlı
´c
ˇek J (2008) Neurophysiological effect of
the Rh factor. Protective role of the RhD molecule against Toxoplasma-induced
impairment of reaction times in women. Neuroendocrinol Lett 29: 475–481.
375. Flegr J, Hampl R, C
ˇernochova´ D, Preiss M, Bic
ˇı
´kova M, et al. (2012) The
relation of cortisol and sex hormone levels to results of psychological,
performance, IQ and memory tests in military men and women. Neuroendo-
crinol Lett 33: 224–235.
376. Overfield J, Hamer D, Dawson M (2007) Introduction to the Rh blood group
system. Oxodshire, U.K.: Scion Publishing.
Correlation of Toxoplasmosis with Disease Burden
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... Bradyzoites can persist inside human cells during protracted periods of time. Remarkably stable oocysts are transmitted to other hosts through inadvertent ingestion [1]. Domestic cats and other felids are the known definitive hosts of the agent and can eliminate viable oocysts through their feces [2]. ...
... T. gondii prevalence in humans varies across countries and regions [2][3][4]. A possible explanation is that T. gondii incidence is higher in regions with higher humidity and temperature, such as South America (prevalence in Brazil reaches 77.5%) [2,4], in the same way that infection by the parasite is lower in some European countries and the Far East [1,4]. This is because the oocysts are more long-lived in humid environments during the parasite's reproduction cycle [1]. ...
... A possible explanation is that T. gondii incidence is higher in regions with higher humidity and temperature, such as South America (prevalence in Brazil reaches 77.5%) [2,4], in the same way that infection by the parasite is lower in some European countries and the Far East [1,4]. This is because the oocysts are more long-lived in humid environments during the parasite's reproduction cycle [1]. ...
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Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii (T. gondii), which is one of the most widespread zoonotic pathogens known today. It is a global health hazard as they infect 30-50% of the world's human population. Acute toxoplasmosis is usually asymptomatic and self-limited in immunocompetent people, recovering without treatment and do not require specific therapy. Therefore, rare complications are associated with infection in the individuals with normal immune systems. However, we present a rare case of an immunocompetent man with acute T. gondii infection confirmed by serology, subsequently presented with two life-threatening organ dysfunctions: severe renal and pulmonary involvement, requiring hospitalization and anti-parasitic treatment.
... Upon contact with oxygen, oocysts will sporulate and lead to infective environmentally resistant oocysts (Ferguson, 2002) that can be consumed by intermediate hosts, including pregnant women. Altogether, these characteristics make T. gondii one of the most successful zoonotic parasites worldwide (Flegr et al., 2014). ...
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Toxoplasma gondii is a ubiquitous apicomplexan parasite that can infect virtually any warm-blooded animal. Acquired infection during pregnancy and the placental breach, is at the core of the most devastating consequences of toxoplasmosis. T. gondii can severely impact the pregnancy’s outcome causing miscarriages, stillbirths, premature births, babies with hydrocephalus, microcephaly or intellectual disability, and other later onset neurological, ophthalmological or auditory diseases. To tackle T. gondii’s vertical transmission, it is important to understand the mechanisms underlying host-parasite interactions at the maternal-fetal interface. Nonetheless, the complexity of the human placenta and the ethical concerns associated with its study, have narrowed the modeling of parasite vertical transmission to animal models, encompassing several unavoidable experimental limitations. Some of these difficulties have been overcome by the development of different human cell lines and a variety of primary cultures obtained from human placentas. These cellular models, though extremely valuable, have limited ability to recreate what happens in vivo. During the last decades, the development of new biomaterials and the increase in stem cell knowledge have led to the generation of more physiologically relevant in vitro models. These cell cultures incorporate new dimensions and cellular diversity, emerging as promising tools for unraveling the poorly understood T. gondii´s infection mechanisms during pregnancy. Herein, we review the state of the art of 2D and 3D cultures to approach the biology of T. gondii pertaining to vertical transmission, highlighting the challenges and experimental opportunities of these up-and-coming experimental platforms.
... Humans, as IH, present a third or more people who have been exposed to infection with T. gondii. The prevalence ranges widely (10-85%) between nations, geographical areas within a country [7], socioeconomic conditions, climate (warm, humid tropical areas, cold-temperate, or desert regions), poor sanitation, a lack of clean water, and poor hygiene [44]. Toxoplasmosis is classified into an acute acquired infection (horizontal transmission) and a congenital infection (CT) [45] with an incubation period from 10 to 23 days after consuming tissue cysts and from 5 to 10 days following the consumption of oocysts [10,46]. ...
... Humans, as IH, present a third or more people who have been exposed to infection with T. gondii. The prevalence ranges widely (10-85%) between nations, geographical areas within a country [7], socioeconomic conditions, climate (warm, humid tropical areas, cold-temperate, or desert regions), poor sanitation, a lack of clean water, and poor hygiene [44]. Toxoplasmosis is classified into an acute acquired infection (horizontal transmission) and a congenital infection (CT) [45] with an incubation period from 10 to 23 days after consuming tissue cysts and from 5 to 10 days following the consumption of oocysts [10,46]. ...
... Humans, as IH, present a third or more people who have been exposed to infection with T. gondii. The prevalence ranges widely (10-85%) between nations, geographical areas within a country [7], socioeconomic conditions, climate (warm, humid tropical areas, cold-temperate, or desert regions), poor sanitation, a lack of clean water, and poor hygiene [44]. Toxoplasmosis is classified into an acute acquired infection (horizontal transmission) and a congenital infection (CT) [45] with an incubation period from 10 to 23 days after consuming tissue cysts and from 5 to 10 days following the consumption of oocysts [10,46]. ...
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... No entanto, a incidência de infecção é mais elevada em regiões de clima quente e úmido e quando associada às condições precárias de saneamento básico a transmissão do T. gondii se torna mais comum. Estima-se que 30 a 50% da população mundial esteja infectada com o parasito, sendo a toxoplasmose, uma das infecções com maior soroprevalência em humanos [3][4][5] . No Brasil, até 50% das crianças e 80% das mulheres em idade fértil podem apresentar anticorpos para esse protozoário, dependendo da região geográfica 6 . ...
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... [1] More than one-third of the world's population is estimated to be infected with this parasite. [2] T. gondii infection is generally asymptomatic DOI: 10.1002/advs.202206595 in people with normal immunity. However, it can be fatal to infants and immunosuppressed patients, such as organ transplant recipients and patients with AIDS or cancer. ...
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Toxoplasmosis is an infection of vast worldwide distribution whose etiologic agent is Toxoplasma gondii. This disease can cause problems ranging from mild symptoms to serious conditions, such as encephalitis, miscarriage and blindness. Therefore, it is of utmost importance to perform a diagnosis with reproducible techniques in order to obtain a good prognosis. The aim of this review was to analyze the efficiency of toxoplasmosis diagnostic techniques based on sensitivity and specificity results. Five research platforms in English language were used (Eric, Elsevier, Google Scholar, PubMed and SciELO), which contained data on the diagnosis of toxoplasmosis. The search and selection were performed for studies published prior to June 2021. The search resulted in the inclusion of 13 articles published from 2005 to 2020. The data revealed the use of different samples in the standardization of techniques such as serum, total blood, colostrum and amniotic fluid. The flow cytometry, lateral flow immunoassay and qPCR techniques showed 100% sensitivity, whereas the ELISA, western blotting, qPCR and RE-LAMP techniques achieved 100% specificity. Significantly, the qPCR and LAMP techniques were more accurate when the likelihood ratio was assessed. The meta-analysis identified that ISAGA and western blotting have low sensitivity values and LIASON, ELFA and ELISA, using a silica bioconjugate, also have low specificity values. It was noted that a wide range of methods have high values of sensitivity and specificity. Therefore, the choice of the method will be based on the conditions and its financial viability.
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La toxoplasmosis es una enfermedad de alta prevalencia y distribución mundial que puede cursar de forma asintomática, aunque también puede ocasionar clínica grave en personas inmunocomprometidas e incluso ser mortal. Este libro compila información desde la perspectiva “Una salud” contando con la visión de diferentes profesionales implicados en el área: clínicos, epidemiólogos y microbiólogos, lo que proporciona una perspectiva altamente enriquecedora y de gran utilidad para todos aquellos profesionales interesados en esta temática.
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La toxoplasmosis es una enfermedad de alta prevalencia y distribución mundial que puede cursar de forma asintomática, aunque también puede ocasionar clínica grave en personas inmunocomprometidas e incluso ser mortal. Este libro compila información desde la perspectiva “Una salud” contando con la visión de diferentes profesionales implicados en el área: clínicos, epidemiólogos y microbiólogos, lo que proporciona una perspectiva altamente enriquecedora y de gran utilidad para todos aquellos profesionales interesados en esta temática.
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Although parasitic infections do not usually present with disturbance in renal function, glomerular lesions can be seen in most of these infections. The glomerular lesions observed in parasitic infections cover the whole range of glomerular lesions known, but most of them are proliferative. Little is known of the exact pathogenic mechanisms. In this review, we try to explain the glomerular lesions associated with parasitic infections in terms of the specific immunologic events observed during these diseases against the background of recent developments in the general knowledge of the pathogenesis of glomerular disease.
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Toxoplasma gondii (T. gondii) infections can cause serious complications in HIV-infected pregnant women, leading to miscarriage, stillbirth, birth defects (e.g., mental retardation, blindness, epilepsy etc.) and could favor or enhance the mother-to-child transmission of HCV, HBV, and HIV vertical transmission. From May 20, 2004 to August 3, 2005, 336 18–45 years aged pregnant women, were enrolled for an investigation of the prevalence of serum antibodies against T. gondii, HCV, HBV, and HIV using ELISA. The prevalence of T. gondii, HCV, and HBV in pregnant women was 25.3%, 5.4%, and 9.8%, respectively and the HIV serostatus (61.6%) seems to be associated with greater prevalence rates of both T. gondii (28.5% vs. 20.2%) and HBV (11.6% vs. 7.0%). Without taking into account HIV, only 65.5% (220 of 336) of the women were not infected with these agents. The co-infection rate between HIV-infected and -negative women was different statistically: T. gondii/HBV 0.048 versus 0.015, T. gondii/HCV 0.014 versus 0.008, and HCV/HBV 0.005 versus 0.008, respectively. The elevated co-infection rate in HIV-positive women demonstrated that they are exposed to T. gondii, HCV, and HBV infections prevalently by sexual contact. J. Med. Virol. 78:730–733, 2006. © 2006 Wiley-Liss, Inc.
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Background: Toxoplasma gondii is found worldwide, but distribution of its genotypes as well as clinical expression of human toxoplasmosis varies across the continents. Several studies in Europe, North America and South America argued for a role of genotypes in the clinical expression of human toxoplasmosis. Genetic data concerning T. gondii isolates from Africa are scarce and not sufficient to investigate the population structure, a fundamental analysis for a better understanding of distribution, circulation, and transmission. Methodology/Principal Findings: Seropositive animals originating from urban and rural areas in Gabon were analyzed for T. gondii isolation and genotyping. Sixty-eight isolates, including one mixed infection (69 strains), were obtained by bioassay in mice. Genotyping was performed using length polymorphism of 13 microsatellite markers located on 10 different chromosomes. Results were analyzed in terms of population structure by Bayesian statistical modeling, Neighbor-joining trees reconstruction based on genetic distances, F-ST and linkage disequilibrium. A moderate genetic diversity was detected. Three haplogroups and one single genotype clustered 27 genotypes. The majority of strains belonged to one haplogroup corresponding to the worldwide Type III. The remaining strains were distributed into two haplogroups (Africa 1 and 3) and one single genotype. Mouse virulence at isolation was significantly different between haplogroups. Africa 1 haplogroup was the most virulent. Conclusion: Africa 1 and 3 haplogroups were proposed as being new major haplogroups of T. gondii circulating in Africa. A possible link with strains circulating in South and Central America is discussed. Analysis of population structure demonstrated a local spread within a rural area and strain circulation between the main cities of the country. This circulation, favored by human activity could lead to genetic exchanges. For the first time, key epidemiological questions were addressed for the West African T. gondii population, using the high discriminatory power of microsatellite markers, thus creating a basis for further epidemiological and clinical investigations.