ArticlePDF AvailableLiterature Review

Abstract

The influence of sex hormones is recognized to account for the susceptibility and distinct outcomes of diverse infectious diseases. This review discusses several variables including differences in behavior and exposure to pathogens, genetic, and immunological factors. Understanding sex-based differences in immunity during different infectious diseases is crucial in order to provide optimal disease management for both sexes.
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DOI 10.1007/s15010-015-0791-9
Infection
REVIEW
Sex differences in immune responses to infectious diseases
Julia Fischer1,3,4 · Norma Jung1 · Nirmal Robinson2,3 · Clara Lehmann1,4
Received: 10 February 2015 / Accepted: 29 April 2015
© Springer-Verlag Berlin Heidelberg 2015
therefore is a risk factor for autoimmune diseases [4]. The
underlying mechanisms for these sexual differences are
diverse, which includes genetic, epigenetic, and hormonal
determinants of immunity. In this review, we will first dis-
cuss our current understanding of the differential immunity
between the sexes. In the second part, we will review the
current knowledge on sex-based differential immunological
responses during various infections.
Biological background, effects of sex hormones
on immunity
The X chromosome
Differential immunological responses observed in women
and men are attributed to the biased response from X chro-
mosome. The X chromosome is known to harbor majority
of the immune-related genes [3, 5]. The human X chro-
mosome encodes for a number of critical genes involved
in the regulation of immunity, such as Toll-like receptors
(TLR) 7 and 8 that play a central role in sensing viral
pathogens; FOXP3, a transcription factor for regulatory T
cells and CD40L (CD154) [6]. The X chromosome also
codes for crucial microRNAs (miR) that regulate immu-
nity. Among the X-linked microRNAs, miR-233 is widely
studied and has been shown to regulate neutrophil differ-
entiation. Similarly, miR-106A, miR-424, miR542, and
miR-503 have been shown to negatively regulate mono-
cyte differentiation [7]. Further, a large number of X-linked
miRNAs are reported to downregulate negative regulators
of immunity; such as forkhead box P3 (FOXP3), cytotoxic
T-lymphocyte-associated protein 4 (CTLA-4), programmed
cell death 1 (PDCD1) and members of casitas B-lineage
lymphoma (CBL) and suppressors of cytokine signaling
Abstract
Purpose The influence of sex hormones is recognized
to account for the susceptibility and distinct outcomes of
diverse infectious diseases.
Methods This review discusses several variables includ-
ing differences in behavior and exposure to pathogens,
genetic, and immunological factors.
Conclusion Understanding sex-based differences in immu-
nity during different infectious diseases is crucial in order to
provide optimal disease management for both sexes.
Keywords Sex · Immunity · Infectious diseases
Introduction
Sex-based differences on the outcome of numerous infec-
tious diseases are evident from many clinical studies [1].
In general, females show stronger humoral and cellular
immune responses to infection or antigenic stimulation
than the males [2, 3]. This enhanced level of immunity is
a double-edged sword: on one hand, it can provide protec-
tion against several pathogens. On the other hand, this can
lead to an aberrant pathogenic inflammatory response and
* Clara Lehmann
clara.lehmann@uni-koeln.de
1 First Department of Internal Medicine, University
of Cologne, Kerpener Str. 62, 50934 Cologne, Germany
2 Institute for Medical Microbiology, Immunology
and Hygiene, University of Cologne, Cologne, Germany
3 CECAD Research Center, Cologne, Germany
4 German Center for Infection Research (DZIF), Partner Site
Bonn-Cologne, Cologne, Germany
J. Fischer et al.
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(SOCS) family. This is considered to be a cause for preva-
lent autoimmune disorders observed in women [8].
Females harbor two X chromosomes, whereas males
carry one X and one Y chromosome. In order to prevent
excessive responses from the X chromosome, the female
mammals have evolved a complex mechanism termed as
X-inactivation. Through this process one of the X chro-
mosomes is transcriptionally silenced during the develop-
ment process of a female. This leads to cellular mosaicism;
which means that either the X chromosome from paternal
or maternal origin is expressed in different cell popula-
tions. As a result, gene mutation in X-linked chromosome
is expressed in part of the cells in females, whereas all the
cells in males will exhibit the mutation. Cellular mosai-
cism has proven to provide immunological advantage for
the females. Diseases such as X-linked severe combined
immunodeficiency (XSCID) and immune dysregulation [9,
10], polyendocrinopathy, enteropathy, X-linked syndrome
(IPEX) harbor mutations in genes that are linked to the X
chromosome [11]. X-inactivation allows part of the cells to
express the wild type genes in females compared to none
of the cells in males. Therefore, these genetically inherited
diseases are more prevalent in males. In mouse models of
microbial sepsis, animals exhibiting cellular mosaicism for
Interleukin-1 receptor-associated kinase 1 (IRAK1) expres-
sion and NADPH oxidase 2 (NOX2) have shown improved
clinical phenotype in survival and bacterial clearance. Taken
together, inactivation of X chromosome equips females
with a wide reserve of proteins, which provide diversified
and effective immune responses. However, women are at a
higher risk of contracting autoimmune disorders and this is
attributed to gene dosage from X chromosome [6].
Immunomodulatory functions of sex steroid hormones
Sex hormones significantly affect the functions of immune
cells. This is evident from transcriptome analysis of periph-
eral blood monocytes (PBMCs) of men and women of all
ages. Data reveal that age and sex potently alter the tran-
scriptional responses in immune cells. Like other hormones,
sex steroids exert their function by binding to specific
receptors. Immune cells such as lymphocytes and myeloid
cells have been shown to express estrogens receptors (ER),
androgen receptors (AR), and progesterone receptors (PR).
The sex steroid receptors act as nuclear transcription factors
through different ligand-dependent or ligand-independent
mechanisms [12]. The expression of the hormone receptors
on immune cells clearly signifies that they have key immu-
noregulatory functions. The majority of the scientific work
has focused on the ER. Two subtypes of ER, ERα, and ERβ
are known so far and their roles in the immune regulation
are subject of current research. Most immune cells such
as B- and T-lymphocytes, dendritic cells, macrophages,
monocytes, natural killer cells, and mast cells express ERα,
while ERβ is infrequently expressed. The expression of ERs
is autoregulated [13]. ERα and ERβ deficient mice develop
fully established immune system. However, their immune
system becomes disoriented by age. Thus aged ERα knock-
out (ERα/) mice develop autoimmune disorders [14]
and aged ERβ/ mice develop chronic myeloid leukemia
[15]. Moreover, estradiol has been shown to increase both
the humoral and cell-mediated immune responses. Inter-
estingly, estrogen positively regulates TLR-mediated pro-
inflammatory pathways in murine macrophages and plas-
macytoid dendritic cells (pDCs). It enhances the cytotoxic
activity of natural killer cells (NK-cells) and also upregu-
lates pro-inflammatory cytokines such as TNF-α, IL-6, and
IL-1. Estradiol has also been reported to affect the function
of invariant natural killer T cells (iNKT). ERα deficiency,
ovariectomy, or continuous administration of estradiol leads
to altered production of interferon gamma (IFNγ) and IL-4
production [16]. In vivo administration of alpha-galactosyl-
ceramide (iNKT ligand) induces higher cytokine production
in female than in the male mice. However, the effect was not
observed in ovariectomized female mice, suggesting that the
increase in cytokine expression is an effect of estradiol [17].
Androgen Receptors and cognate receptors for proges-
terone have also been detected in immune cells, implicating
a direct effect of androgens on the development and func-
tion of immune system [1820]. However, the underlying
mechanisms are not well understood. Contrary to estrogens,
androgen and progesterone are known to be anti-inflamma-
tory. Testosterone reduces NK-cell activity and the secretion
of pro-inflammatory cytokines by downregulating NF-κB
signaling, but increases the production of anti-inflammatory
cytokines. It is also known to suppress the expression of
TLRs upon infection. Similar to testosterone, progesterone
also inhibits NF-κB-mediated pro-inflammatory cytokines
and increases anti-inflammatory signatures. During preg-
nancy, progesterone has been reported to skew the T cell
responses toward Th2 response [6]. This could partly explain
why pregnant women are more susceptible to infections such
as Listeria monocytogenes, Rubella virus, and Toxoplasma
gondii. Considering the differential immunoregulatory prop-
erties of sex steroid hormones, it is perceivable that hormo-
nal changes during menstrual cycle, menopause, and preg-
nancy could greatly influence the immune responses.
Viral infections
Human immunodeficiency virus
In the context of Human immunodeficiency virus (HIV)
infection, sex-based differences in the course of disease
progression have been reported: women have lower plasma
Sex differences in immune responses to infectious…
1 3
viral loads, higher CD4+ T cell counts, and higher risk of
progressing to AIDS than men [2123]. Moreover, women
are more prone to anti-retroviral drug-induced adverse
effects. Therefore, it has been suggested to revise treatment
recommendations for women and men [24, 25].
Persistent chronic inflammation in women contributes to
immune pathology and impairment of the immune system.
This could explain the faster disease progression observed
in chronically infected women despite similar pace of viral
replication compared to men. Meier et al. could demon-
strate that women have higher TLR-7-mediated response
of pDCs. This leads to elevated expression of interferon
alpha (IFN-α) and IFN-Stimulated Genes (ISGs) result-
ing in stronger secondary activation of CD8+ T cells [26].
IFN-alpha is known for its antiviral and immunomodula-
tory function but it also can cause immunopathologies [27].
Therefore, in HIV-infected women, IFN-α could be benefi-
cial through its antiviral activity, but in it might also have
deleterious contributions to chronic immune activation
associated with HIV disease progression.
Moreover, studies in rhesus macaques have also shown
differential susceptibility to intravaginal SIV infection dur-
ing luteal phase (high progesterone levels) compared to that
of the follicular phase (high estrogen levels) [28]. However,
understanding the underlying mechanisms involved in the
regulation of immune responses by sex hormones during
long-term HIV disease is crucial in order to develop indi-
vidualized treatment concepts that take sex-specific host
factors into account.
Hepatitis C
Numerous studies have demonstrated that women are more
likely to spontaneously clear Hepatitis C Virus (HCV) during
acute infection than males [29]. Moreover, the risk of cirrhosis
is higher for men than women during chronical stage of HCV
infection [30]. However, after menopause the sex differences
in chronic HCV disease are attenuated. Di Martino et al. [31]
observed that the accelerated rates of cirrhosis and fibrotic
progression in postmenopausal female can be prevented
through hormone substitution therapy. These differences in
clinical outcomes during the acute and chronic phase of infec-
tion could in part be explained by the increased response of
the TLR7/8 signaling pathway which in the context of HCV
infection proves to be beneficial. However, further research
is required to better understand the mechanisms behind the
potential effect of female sex on HCV viral control [29].
Bacterial infections
In General, men are more susceptible to bacterial infec-
tions than women. Thus, sex determinants are considered
to play a key role in immune response against bacterial
infections such as Mycobacterium spp., Listeria mono-
cytogenes, Treponema pallidum, Staphylococcus aureus,
Pseudomonas aeruginosa, Vibrio vulnificus, Borrelia burg-
dorferi, and Escherichia coli [32, 33].
In 2012, the analysis of the tuberculosis notification data
revealed a male-to-female ratio of 1.9:1 [34], which has
been consistent with the data from earlier years [35, 36].
Behavioral and physiological reasons are being discussed
as explanations. With regard to behavioral factors, smoking,
alcohol consumption, and mine-related silicosis, especially
in countries with high bacterial burden are correlated with
male sex. To study the physiological sex differences, animal
models have been used. One study demonstrated that fertile
male mice were more susceptible to infection with Myco-
bacterium marinum and Mycobacterium intracellulare.
Male mice exhibited severe disease pathology compared to
castrated male mice [37]. Few studies have examined sex
differences in humans. A study in patients of an American
institution for mentally ill patients showed that only 8.1 %
of castrated men died from tuberculosis compared to 20.6 %
of intact males. Another study in young Swedish women
who underwent oophorectomy due to salpingitis found that
the tuberculosis mortality rate increased to 7 % compared
to 0.7 % [38]. These differences are thought to be X-linked
immune responses. In mouse models of Mycobacterium spp
infections, the resistance offered by female mice has been
attributed to better anti-bacterial activity of macrophages
[39]. The susceptibility of male mice has been linked to
decreased production of antibodies against lipoarabinoman-
nan (lipid present in mycobacterial cell wall) [40].
Syphilis caused by Treponema pallidum also has been
reported to show sexual dimorphism. The resistance shown
by females has been correlated with increased CD4+ and
CD8+ T-cells [41]. Similarly, it has been observed that
females are more resistant to other bacterial infections
such as Staphylococcus aureus, Pseudomonas aeruginosa,
Vibrio vulnificus, Borrelia burgdorferi. Conversely, females
are susceptible to E. coli bacteremia. This bias is perhaps
due to E. coli associated urinary tract infection prevalent in
women. Women are prone to Listeria infection. It has been
reported that the susceptibility of mice to Listeria is linked
to increased IL-10 secretion by female mice. Female non-
obese diabetic mice have a higher incidence of developing
type I diabetes. This increased incidence is linked to the
difference in beneficial microbes colonizing the gut of male
and female mice. This trend was reversed by male castra-
tion, meaning androgens influence gut microbiota [42].
Thus sexual dimorphism plays a key role in the resistance
mechanisms against pathogens and maintaining a healthy
microbiota in the gut. However, to date there are no stud-
ies which define a complete explanatory mechanism for the
sexual dimorphism exhibited during infection.
J. Fischer et al.
1 3
Parasitic infections
Parasites are phylogenetically diverse and they target dif-
ferent tissues. The influence of female and male sex hor-
mones on the immune responses toward different parasitic
infections is pathogen specific [43]. In studies which ana-
lyzed the sex-based differences in immunity toward dif-
ferent parasitic infections, males were found to be more
resistant to Trichomonas vaginalis [44] and Toxoplasma
gondii [45], while females were more resistant to infec-
tions with Leishmaniasis [46, 47], Trypanosoma cruzi and
Trypanosoma brucei [48], Giardia lamblia, and Schisto-
soma mansoni [49]. Animal models have been conducted
to analyze the sex-related differences in parasitic infection.
For instance, it was shown that testosterone influences the
disease outcome of Leishmania infection by affecting anti-
gen-presenting cells and T cells as well as rising an anti-
inflammatory T-helper 2 (Th2) response. In comparison
to females, male rodents present more lesions and higher
parasite burdens. This observation was explained by an
increased Th2 response including an augmented mRNA
expression of interleukin 4 (IL-4), interleukin 10 (IL-10),
transforming growth factor (TNF) β, and TNF-α [50, 51].
Moreover, the resistance of female hamsters toward Leish-
mania mexicana correlated with an increased expression of
IFNγ [50]. Overall, using Leishmania as a parasitic model
provides insights into how sex hormones can influence
immunological mechanisms.
Conclusions
Males have a higher susceptibility to many infectious path-
ogens compared to women. This can in part be explained
by stronger Th1 immune responses in women. However, in
some infections, females are at a risk of developing intensi-
fied immunopathology due to higher levels of pro-inflam-
matory immune responses (e.g., HIV infection). Never-
theless, this simplification does not apply to all infectious
conditions. Thus, as recognized by the National Institute of
Health (NIH), the significance of including sex as a criteria
in studies conducted with human subjects or on material of
human origin is mandatory to improve a better understand-
ing of the sex-related differences in immunity to infections
(NIH Policy and guideline on the inclusion and minori-
ties as subjects in Clinical Research, amended October,
accessed January 2015, [52].
Acknowledgements This review was written in honor of Gerd Fät-
kenheuer’s 60th birthday. He has been our teacher for over a decade
and we would like to thank him for his excellent teaching—both in
internal medicine and infectious diseases but also in science and poli-
tics. He taught us to systematically look for all the puzzle pieces, to
find a plausible diagnosis, to never give up, to take responsibility for
our decisions, and to never forget the ultimate goal—the best for the
patient. CL and JF are supported by the German Centre for Infec-
tion Research (DZIF). NR’s research is supported by funding from
Cologne Excellence Cluster on Cellular Stress Responses in Aging-
Associated Diseases (CECAD; funded by the DFG within the Excel-
lence Initiative by the German federal and state governments) and
Deutsche Forschungsgemeinschaft (SFB 670).
Conflict of interest The authors have no conflicts of interest.
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... Sex-related differences shaped by multidimensional biological characteristics that define females and males exert considerable influence on the pathogenesis of various human diseases (Klein and Flanagan, 2016), including autoimmune diseases (Jacobson et al., 1997), cancers (Cook et al., 2009(Cook et al., , 2011Kim et al., 2018), and infectious diseases caused by diverse pathogens (vom Steeg and Klein, 2016;Fischer et al., 2015;Sawyer, 2012). Each infectious disease exhibits a distinct pattern of sex bias in the prevalence, intensity, and outcome of infections (vom Steeg and Klein, 2016;Giefing-Krô ll et al., 2015), as well as in the responses to antiviral drugs and vaccines (Klein, 2012;Morgan and Klein, 2019). ...
... These intricate differences in immune functions between sexes have a powerful impact on infectious disease pathogenesis. For example, an augmented response to pathogens in females allows better control and clearance of pathogens while promoting increased immunopathology (vom Steeg and Klein, 2016;Klein, 2012;Fischer et al., 2015). During influenza infections, female mice exhibited a more robust induction of pro-inflammatory cytokines and chemokines in their lungs, including TNF-a, IFN-b, IL-6, and CCL2, accompanied by greater weight loss, hypothermia, and mortality than male mice . ...
... Although the microbiome (Markle et al., 2013;Yurkovetskiy et al., 2014, Vom Steeg andKlein, 2017;Vemuri et al., 2019) and nutritional status (Khulan et al., 2012;Tobi et al., 2009;Sinha et al., 2003;Kawai et al., 2010;Osrin et al., 2005;Christoforidou et al., 2019) have been implicated in modulating immune responses, sex hormones and genetic mediators are the most widely appreciated factors shaping differential immunity between females and males. In addition to the profound effects of sex hormones that have been extensively demonstrated, genetic differences attributed to immune-related genes and microRNAs (miRNAs) that are located on the sex chromosomes also play an important role in determining the distinct immune responses between sexes, especially in prepubertal children, postmenopausal females, and age-matched males (reviewed in (Galligan and Fish, 2015;Klein and Flanagan, 2016;Fischer et al., 2015;Fish, 2008;Klein, 2000;vom Steeg and Klein, 2016;Schurz et al., 2019;Bianchi et al., 2012)). However, the pathways and cellular responses that mediate the differences in response to influenza infection have not been well elucidated. ...
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Sex differences in the pathogenesis of infectious diseases due to differential immune responses between females and males have been well documented for multiple pathogens. However, the molecular mechanism underlying the observed sex differences in influenza virus infection remains poorly understood. In this study, we used a network-based approach to characterize the blood transcriptome collected over the course of infection with influenza A virus from female and male ferrets to dissect sex-biased gene expression. We identified significant differences in the temporal dynamics and regulation of immune responses between females and males. Our results elucidate sex-differentiated pathways involved in the unfolded protein response (UPR), lipid metabolism, and inflammatory responses, including a female-biased IRE1/XBP1 activation and male-biased crosstalk between metabolic reprogramming and IL-1 and AP-1 pathways. Overall, our study provides molecular insights into sex differences in transcriptional regulation of immune responses and contributes to a better understanding of sex biases in influenza pathogenesis.
... Another study of mice detected higher proinflammatory cytokine levels in male mice during infection with Streptococcus pneumoniae [33]. The mortality advantage or disadvantage due to different immune response for males or females depends on the kind of pathogen causing different types of pneumonia: for example, VAP/HAP being most likely caused by bacteria [34,35]. ...
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Background and Objectives: The impact of sex on mortality in patients with pneumonia requiring intensive care unit (ICU) treatment is still a controversial discussion, with studies providing heterogeneous results. The reasons for sex differences are widespread, including hormonal, immunologic and therapeutic approaches. This study’s aim was to evaluate sex-related differences in the mortality of ICU patients with pneumonia. Material and Methods: A prospective observational clinical trial was performed at Charité University Hospital in Berlin. Inclusion criteria were a diagnosis of pneumonia and a treatment period of over 24 h on ICU. A total of 436 mainly postoperative patients were included. Results: Out of 436 patients, 166 (38.1%) were female and 270 (61.9%) were male. Significant differences in their SOFA scores on admission, presence of immunosuppression and diagnosed cardiovascular disease were observed. Male patients were administered more types of antibiotics per day (p = 0.028) at significantly higher daily costs (in Euros) per applied anti-infective drug (p = 0.003). Mortalities on ICU were 34 (20.5%) in females and 39 (14.4%) in males (p = 0.113), before correcting for differences in patient characteristics using logistic regression analysis, and afterwards, the female sex showed an increased risk of ICU mortality with an OR of 1.775 (1.029–3.062, p = 0.039). Conclusions: ICU mortality was significantly higher in female patients with pneumonia. The identification of sex-specific differences is important to increase awareness among clinicians and allow resource allocation. The impact of sex on illness severity, sex differences in infectious diseases and the consequences on treatment need to be elucidated in the future.
... As we all know, men and women are behaviorally, socially, and biologically distinct [11]. ese disparities can be linked to men's higher exposure to the outside environment than women's [12,13] as well as testosterone's effect on most parasite diseases [14][15][16]. e age range of 61-70 years was associated with the highest rate of involvement in our study, which was in line with the findings of other studies [1,2,9]. However, multiple studies have reported the presence of L. blattarum infection in children [17][18][19][20], indicating the possibility of two age peaks of disease, which could be explained by the altered immune systems of these two age groups [21]. ...
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Background: Lophomonas blattarum is an emerging protozoan agent that mainly infects the lower respiratory system, causing pulmonary lophomoniasis. The bronchoscopic findings in patients with pulmonary lophomoniasis have not been investigated yet. Accordingly, we assess the bronchoscopic findings of lophomoniasis in patients suffering from pulmonary lophomoniasis through a registry-based clinical study. Methods: In this retrospective study, of 480 patient candidates for bronchoscopy, 50 Lophomonas-positive patients were enrolled. Demographic data, relevant characteristics, and bronchoscopy findings of the patients were recorded and analyzed. Results: Overall, 50 (male = 32, female = 18) patients with an average age of 61.8 ± 13.3 years were examined. Nineteen patients (38%) had normal bronchoscopic findings, and 31 patients (62%) had abnormal bronchoscopic findings. According to the severity index, most (52%) of patients had mild severity, followed by moderate (30%) and severe (18%) cases. The highest involvement was in the right lung bronchus (46%), and the lowest was in the carina (8%). Furthermore, purulent and mucosal secretions in the right and left lung bronchus were the most abnormalities found in different anatomical locations. Conclusion: For the first time, the current study demonstrated that pulmonary lophomoniasis does not have pathognomonic bronchoscopic findings. However, each suspected patient must be checked for lophomoniasis, even with normal bronchoscopic findings, particularly in endemic areas.
... Studies of HIV in CW have revealed faster progression to AIDS compared to men with HIV and similar viral loads, as well as altered levels of plasma markers of microbial and immune activation after treatment among CW versus CM with HIV (57,58). These differences may be explained by estrogen's ability to modulate TLR-mediated pro-inflammatory pathways, which contribute to chronic immune activation associated with CV morbidity and mortality (57)(58)(59)(60)(61). The addition of 17-b estradiol tended to enhance LPS-induced expression of the activation marker HLA-DR on monocytes, and production of cytokines IL-6 and TNF-a from the PBMCs of PWH regardless of ART status; enhancement of these molecules by the addition of estrogen was reduced in those without HIV. ...
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Background Transgender women (TW) are at increased risk for both human immunodeficiency virus (HIV) and cardiovascular disease (CVD). Antiretroviral therapy-treated HIV has been associated with a two-fold increased risk of CVD, potentially due to dysregulated Toll-like receptor (TLR)-induced immune activation. Use of estrogens in feminizing hormone therapy (FHT) may enhance inflammatory responses and the risk of cardiovascular mortality in TW. Despite this, the immunomodulatory effects of estrogen use in TW with HIV have been inadequately explored. Methods As an in vitro model for FHT, cryopreserved PBMCs (cryoPBMCs) from HIV negative (HIV-), HIV+ ART-suppressed (HIV+SP), and HIV+ ART-unsuppressed (HIV+USP) cisgender men were cultured overnight in the presence of 17-β estradiol or 17-α ethinylestradiol with and without the TLR4 agonist LPS or the TLR8 agonist ssPolyU. Monocyte activation (CD69, HLA-DR, CD38) was assessed by flow cytometry. Cytokine levels (IL-6, TNF-α, IL-1β, and IL-10) were measured in cell culture supernatants by Legendplex. Levels of phosphorylated TLR signaling molecules (JNK, MAPK p38) were assessed by Phosflow. Plasma levels of immune activation biomarkers (LPS-binding protein, monocyte activation markers sCD14 and sCD163, and inflammatory molecules IL-6 and TNF-α receptor I) were measured by ELISA. Results PBMCs from people with HIV (PWH) produced greater levels of inflammatory cytokines following exposure to LPS or ssPolyU compared to levels from cells of HIV- individuals. While estrogen exposure alone induced mild changes in immune activation, LPS-induced TLR4 activation was elevated with estrogen in cisgender men (CM) with HIV, increasing monocyte activation and inflammatory cytokine production (IL-6, TNF-α). Interestingly, testosterone inhibited LPS-induced cytokine production in CM regardless of HIV status. Plasma markers of immune activation and microbial translocation (e.g., sCD14, sCD163, LPS-binding protein) were generally higher in PWH compared to HIV- CM, and these markers were positively associated with in vitro responsiveness to estrogen and LPS in CM with HIV. Conclusions Our in vitro data suggest that estrogen exposure may enhance innate immune activation in PWH. Further examination is needed to fully understand the complex interactions of FHT, HIV, and CVD in TW, and determine optimal FHT regimens or supplementary treatments aimed at reducing excess immune activation.
... As we all know [16], men and women are behaviorally and biologically different. ese differences can be attributed to men's increased exposure to the outside environment compared to women's exposures [17,18], as well as testosterone's impact on the majority of parasitic infections [19][20][21]. ...
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Objectives: Lophomonas protozoan is an emerging pathogen transmitted through arthropods such as cockroaches. Lophomoniasis is still a mysterious disease with many unknown epidemiological aspects. The current study aimed to determine the prevalence of lophomoniasis among patients who were hospitalized in Hajar Hospital, Shahrekord, southwestern Iran, using a conventional PCR technique. Methods: In this retrospective study, 132 frozen bronchoalveolar lavage fluid (BALF) specimens from patients with respiratory disorders hospitalized in Hajar Hospital, Shahrekord district, southwestern Iran, were analyzed during 2020-2021. Samples are referred to the Iranian National Registry Center for Lophomoniasis (INRCL), Mazandaran Province, Northern Iran, for detecting Lophomonas spp. infection by a conventionally small subunit ribosomal RNA (SSU rRNA) PCR test. Results: A total of 132 frozen BALF specimens were examined, 36 (27.3%) tested Lophomonas spp. positive using the conventional PCR technique. Also, based on sequencing data and blast analysis, the presence of L. blattarum species was confirmed. The average age of Lophomonas spp.- positive patients was 67.02 ± 15.14 years. Out of the 36 positive subjects, 63.9% were male and 36.1% female. Male and Lophomonas infection had a significant correlation (p=0.001). Our findings revealed that L. blattarum infected nonsmokers more than smokers (p=0.001). The most common underlying disease was also bronchitis. Conclusion: Our results showed, for the first time, that pulmonary lophomoniasis caused by L. blattarum is a common and emerging disease in the study area, southwestern Iran. Furthermore, our findings support the use of the PCR test to detect Lophomonas infection in archived frozen clinical samples.
... There is a strong association between ACE2 expression and COVID-19 infection, susceptibility, severity, and fatality. Higher expression of ACE2 in males compared to females is one of the factors related to the severe symptoms and even death of COVID-19 infection (Liu et al., 2010;Fischer et al., 2015). In females, the X-inactivation mechanism (XCI) is the main factor for the sex-dependent expression of ACE2. ...
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The coronavirus-related severe acute respiratory syndrome (SARS-CoV) in 2002/2003, the Middle East respiratory syndrome (MERS-CoV) in 2012/2013, and especially the current 2019/2021 severe acute respiratory syndrome-2 (SARS-CoV-2) negatively affected the national health systems worldwide. Different SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and recently Omicron (B.1.1.529), have emerged resulting from the high rate of genetic recombination and S1-RBD/S2 mutation/deletion in the spike protein that has an impact on the virus activity. Furthermore, genetic variability in certain genes involved in the immune system might impact the level of SARS-CoV-2 recognition and immune response against the virus among different populations. Understanding the molecular mechanism and function of SARS-CoV-2 variants and their different epidemiological outcomes is a key step for effective COVID-19 treatment strategies, including antiviral drug development and vaccine designs, which can immunize people with genetic variabilities against various strains of SARS-CoV-2. In this review, we center our focus on the recent and up-to-date knowledge on SARS-CoV-2 (Alpha to Omicron) origin and evolution, structure, genetic diversity, route of transmission, pathogenesis, new diagnostic, and treatment strategies, as well as the psychological and economic impact of COVID-19 pandemic on individuals and their lives around the world.
... Testosterone is known to suppress the immune system, while estrogen can promote it; this could be why women have a stronger immune response against bacteria and viruses. [14][15][16] Our findings agree with similar previous studies. 13,17 Our results also indicate that the death rate was significantly higher among people with diabetes and chronic diseases. ...
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Background: COVID-19 primarily presents as a respiratory tract infection, but studies indicate that it could be considered a systemic disease that can spread to affect multiple organ systems, including respiratory, cardiovascular, gastrointestinal, hematopoietic, neurological, and immune systems. Objective: To describe and analyze the clinical and hematological characteristics of 300 hospitalized COVID-19 patients in Erbil, Kurdistan. Methods: This retrospective study included 300 patients of any age admitted to hospital due to confirmed COVID-19 between September 2020 and February 2021. Cases were diagnosed by reverse transcriptase polymerase chain reaction assays of nasopharyngeal swab specimens. Results: The highest proportion of patients were aged 21-40 years. The most common symptoms among the patients were myalgia (66.7%), fatigue (62.3%), headache (50.7%), and chest pain (52.7%). Differences in hematological and biochemical parameters were observed between deceased and recovered patients. Only the mid-range absolute count percentage (MID%) was significantly higher in the recovered patients than in the deceased ones (6.41% vs. 4.48, p = 0.019). Death was significantly higher among older patients (>40 years) than younger ones (≤40 years) (6.8% vs. 1.3%, p = 0.015), diabetic than non-diabetic (10.8% vs. 3%, p = 0.047), and those having chronic diseases than those without chronic diseases (10.6% vs. 2.1%, p = 0.006). Conclusions: Different hematological and biochemical parameter findings were observed among the COVID-19 patients. Low MID%, older age, and presence of diabetes mellitus and chronic disease were significantly associated with death among COVID-19 patients.
... POD was more seen in males, which is in line with the literature [45]. It is likely that men are more at risk for neuroinflammation because of a more active immune system [46]. In our current study, males had higher comorbidity and complications rates and females were more often frail. ...
Article
Introduction: Post-operative delirium (POD) is associated with increased morbidity and mortality rates in older patients. Neuroinflammation, the activation of the intrinsic immune system of the brain, seems to be one of the mechanisms behind the development of POD. The aim of this study was to explore the association between the perioperative inflammatory response and the development of POD in a cohort of older oncological patients in need for surgery. Methods: In this prospective cohort study, patients 65 years and older in need for oncologic surgery were included. Inflammatory markers C-reactive protein (CRP), interleukin-1 beta (IL-1β), IL-6, IL10 and Neutrophil gelatinase-associated lipocalin (NGAL) were measured in plasma samples pre- and post-operatively. Delirium Observation Screening Scale (DOS) was used as screening instrument for POD in the first week after surgery. In case of positive screening, diagnosis of POD was assessed by a clinician. Results: Between 2010 and 2016, plasma samples of 311 patients with median age of 72 years (range 65-89) were collected. A total of 38 (12%) patients developed POD in the first week after surgery. The perioperative increase in plasma levels of IL-10 and NGAL were associated with POD in multivariate logistic regression analysis (OR 1.33 [1.09-1.63] P = 0.005 and OR 1.30 [1.03-1.64], P = 0.026, respectively). The biomarkers CRP, IL-1β and IL-6 were not significantly associated with POD. Conclusions: Increased surgery-evoked inflammatory responses of IL-10 and NGAL are associated with the development of POD in older oncological patients. The outcomes of this study contribute to understanding the aetiology of neuroinflammation and the development of POD.
Article
Context A sex discordance in COVID exists, with males disproportionately affected. Although sex steroids may play a role in this discordance, no definitive genetic data exist to support androgen-mediated immune suppression for viral susceptibility, nor for adrenally produced androgens. Objective The common adrenal-permissive missense-encoding variant HSD3B1(1245C) that enables androgen synthesis from adrenal precursors and that has been linked to suppression of inflammation in severe asthma was investigated in COVID susceptibility and outcomes reported in the UK Biobank. Methods The UK Biobank is a long-term study with detailed medical information and health outcomes for over 500,000 genotyped individuals. We obtained COVID test results, inpatient hospital records, and death records and tested for associations between COVID susceptibility or outcomes and HSD3B1(1245A/C) genotype. Primary analyses were performed on the UK Biobank Caucasian cohort. The outcomes were identification as a COVID case among all subjects, COVID positivity among COVID-tested subjects, and mortality among subjects identified as COVID cases. Results Adrenal-permissive HSD3B1(1245C) genotype was associated with identification as a COVID case (odds ratio 1.11 per C allele, p=0.0013) and COVID test positivity (OR 1.10, p=0.011) in older (≥ 70 years of age) women. In women identified as COVID cases, there was a positive linear relationship between age and 1245C allele frequency (p < 0.0001). No associations were found between genotype and mortality, or between genotype and circulating sex hormone levels. Conclusion Our study suggests that a common androgen synthesis variant regulates immune susceptibility to COVID infection in women, with increasingly strong effects as women age.
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Several important sex and gender differences in the clinical manifestation of diseases have been known for a long time but are still underestimated. The infectious Coronavirus 2019 disease pandemic has provided evidence of the importance of a sex and gender-based approach; it mainly affected men with worse symptomatology due to a different immune system, which is stronger in women, and to the Angiotensin-converting enzyme 2 and Transmembrane protease serine 2 roles which are differently expressed among the sexes. Additionally, women are more inclined to maintain social distance and smoke less. Analysis of data on the infectious Coronavirus 2019 disease testing from people admitted to the Amedeo di Savoia Hospital, a regional referral center for infectious diseases, has been applied to the whole of 2020 data (254,640 records). A high percentage of data in the dataset was not suitable due to a lack of information or entering errors. Among the suitable samples, records have been analyzed for positive/negative outcomes, matching records for unique subjects (N = 123,542), to evaluate individual recurrence of testing. Data are presented in age and sex-disaggregated ways. Analyses of the suitable sample also concerned the relation between testing and hospital admission motivation and symptoms. Our analysis indicated that a sex and gender-based approach is mandatory for patients and the National Health System’s sustainability.
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To the Editor—The journal's recent supplement on sex differences in susceptibility and response to infectious diseases was an excellent initiative for promoting research on a neglected topic of major interest [1–8]. If, in general, males show a higher susceptibility to many infectious diseases, the reviews displayed a number of infectious and autoimmune diseases for which females are more vulnerable. Differential vulnerability between males and females may come from exposure, infection (local or systemic), immune reaction, or a combination of these factors. Evidence came mainly from medicine, epidemiology (direct observation), and biology (animal models and in vivo observation). I address another dimension: demographic evidence.
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Background & objectives: Leishmaniasis has an annual incidence of 0.5-1.5 million new cases and is endemic in 88 countries throughout the world. About 90% of cases of cutaneous leishmaniasis (CL) are reported from seven countries including Iran. Evidence suggests the increased annual incidence of this disease in Iran. Intracellular protozoan parasite, Leishmania, is an obligatory parasite. Sandflies transfer infectious forms of the parasite or its metacyclic promastigotes to its vertebrate hosts such as humans by biting. In order to review the epidemiology of CL in Isfahan, Iran, factors such as incidence, disease causes, geographic features, age, and sex distribution, nationality, and occupation of patients, and the clinical spectrum of disease were evaluated. Methods: During the study, 1315 patients with CL, who referred to the Dermatology and Leishmaniasis Research Center at Isfahan, were evaluated. Results: The highest prevalence of CL was observed in fall (54%) and in northern areas of Isfahan (60.9%). Although CL was prevalent in both men and women, it had higher incidence in men (61.8%). The majority of patients (31.2%) aged 21-30 yr old. Most lesions were nodule-shaped (36.5%) and in upper extremities (48.3%) particularly in men (32.4%). While 81.2% of the subjects were Iranian, others were Afghani or with other nationalities. Most patients had multiple lesions on their bodies and 141 individuals (10.7%) had a previous history of disease. Among all occupations, the highest prevalence of CL was detected in students (18.1%). The response to treatment with compounds of meglumine antimoniate (glucantime) was better than other treatments. Interpretation & conclusion: Unfortunately, the results showed that the prevalence of CL has been increasing annually in some provinces of Iran, especially in Isfahan Province. Nevertheless, further studies are required to determine the vectors, reservoirs, and species of disease and to design appropriate strategies to control the disease.
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Infectious disease incidence is often male-biased. Two main hypotheses have been proposed to explain this observation. The physiological hypothesis (PH) emphasizes differences in sex hormones and genetic architecture, while the behavioral hypothesis (BH) stresses gender-related differences in exposure. Surprisingly, the population-level predictions of these hypotheses are yet to be thoroughly tested in humans. For ten major pathogens, we tested PH and BH predictions about incidence and exposure-prevalence patterns. Compulsory-notification records (Brazil, 2006-2009) were used to estimate age-stratified ♂:♀ incidence rate ratios for the general population and across selected sociological contrasts. Exposure-prevalence odds ratios were derived from 82 published surveys. We estimated summary effect-size measures using random-effects models; our analyses encompass ∼0.5 million cases of disease or exposure. We found that, after puberty, disease incidence is male-biased in cutaneous and visceral leishmaniasis, schistosomiasis, pulmonary tuberculosis, leptospirosis, meningococcal meningitis, and hepatitis A. Severe dengue is female-biased, and no clear pattern is evident for typhoid fever. In leprosy, milder tuberculoid forms are female-biased, whereas more severe lepromatous forms are male-biased. For most diseases, male bias emerges also during infancy, when behavior is unbiased but sex steroid levels transiently rise. Behavioral factors likely modulate male-female differences in some diseases (the leishmaniases, tuberculosis, leptospirosis, or schistosomiasis) and age classes; however, average exposure-prevalence is significantly sex-biased only for Schistosoma and Leptospira. Our results closely match some key PH predictions and contradict some crucial BH predictions, suggesting that gender-specific behavior plays an overall secondary role in generating sex bias. Physiological differences, including the crosstalk between sex hormones and immune effectors, thus emerge as the main candidate drivers of gender differences in infectious disease susceptibility.
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The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli.
Article
Numerous investigations have revealed a bias toward males in the susceptibility to and severity of a variety of infectious diseases, especially parasitic diseases. Although different external factors may influence the exposure to infection sources among males and females, one recurrent phenomenon indicative of a hormonal influence is the simultaneous increase in disease occurrence and hormonal activity during the aging process. Substantial evidence to support the influence of hormones on disease requires rigorously controlled human population studies, as well as the same sex dimorphism being observed under controlled laboratory conditions. To date, only very few studies conducted have fulfilled these criteria. Herein, we introduce tropical infectious diseases, including amebiasis, malaria, leishmaniasis, toxoplasmosis, schistosomiasis, and paracoccidioidomycosis, in which hormones are suspected to play a role in disease processes. We summarize the most recent findings from epidemiologic studies in humans and from hormone replacement studies in animal models, as well as data regarding the influence of hormones on immune responses underlying the pathology of the diseases.
Article
Unlabelled: Although 20%-40% of persons with acute hepatitis C virus (HCV) infection demonstrate spontaneous clearance, the time course and factors associated with clearance remain poorly understood. We investigated the time to spontaneous clearance and predictors among participants with acute HCV using Cox proportional hazards analyses. Data for this analysis were drawn from an international collaboration of nine prospective cohorts evaluating outcomes after acute HCV infection. Among 632 participants with acute HCV, 35% were female, 82% were Caucasian, 49% had interleukin-28 (IL28)B CC genotype (rs12979860), 96% had injected drugs ever, 47% were infected with HCV genotype 1, and 7% had human immunodeficiency virus (HIV) coinfection. Twenty-eight percent were HCV antibody negative/RNA positive at the time of acute HCV detection (early acute HCV). During follow-up, spontaneous clearance occurred in 173 of 632, and at 1 year after infection, 25% (95% confidence interval [CI]: 21, 29) had cleared virus. Among those with clearance, the median time to clearance was 16.5 weeks (IQR: 10.5, 33.4), with 34%, 67%, and 83% demonstrating clearance at 3, 6, and 12 months. Adjusting for age, factors independently associated with time to spontaneous clearance included female sex (adjusted hazards ratio [AHR]: 2.16; 95% CI: 1.48, 3.18), IL28B CC genotype (versus CT/TT; AHR, 2.26; 95% CI: 1.52, 3.34), and HCV genotype 1 (versus non-genotype 1; AHR: 1.56; 95% CI: 1.06, 2.30). The effect of IL28B genotype and HCV genotype on spontaneous clearance was greater among females, compared to males. Conclusions: Female sex, favorable IL28B genotype, and HCV genotype 1 are independent predictors of spontaneous clearance. Further research is required to elucidate the observed sex-based differences in HCV control.
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The significant contributions of sex to an immune response, specifically in the context of the sex bias observed in susceptibility to infectious and autoimmune diseases and their pathogenesis, have until recently, largely been ignored and understudied. This review highlights recent findings related to sex-specific factors that provide new insights into how sex determines the transcriptome, the microbiome, and the consequent immune cell functional profile to define an immune response. Unquestionably, accumulating data confirm that sex matters and must be a consideration when decisions around therapeutic intervention strategies are developed.
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Gender bias and the role of sex hormones in autoimmune diseases are well established. In specific pathogen-free nonobese diabetic (NOD) mice, females have 1.3-4.4 times higher incidence of type 1 diabetes (T1D). Germ-free (GF) mice lost the gender bias (female-to-male ratio 1.1-1.2). Gut microbiota differed in males and females, a trend reversed by male castration, confirming that androgens influence gut microbiota. Colonization of GF NOD mice with defined microbiota revealed that some, but not all, lineages overrepresented in male mice supported a gender bias in T1D. Although protection of males did not correlate with blood androgen concentration, hormone-supported expansion of selected microbial lineages may work as a positive-feedback mechanism contributing to the sexual dimorphism of autoimmune diseases. Gene-expression analysis suggested pathways involved in protection of males from T1D by microbiota. Our results favor a two-signal model of gender bias, in which hormones and microbes together trigger protective pathways.