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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.
1 3
(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 [18–20]. 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 [21–23]. 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.
References
1. Garenne M. Demographic evidence of sex differences in vulner-
ability to infectious diseases. J Infect Dis. 2015;211:331–2.
2. Klein SL. Sex differences in prophylaxis and therapeu-
tic treatments for viral diseases. Handb Exp Pharmacol.
2012;214:499–522.
3. Markle JG, Fish EN. SeXX matters in immunity. Trends Immu-
nol. 2014;35:97–104.
4. Amur S, Parekh A, Mummaneni P. Sex differences and genomics
in autoimmune diseases. J Autoimmun. 2012;38:J254–65.
5. Libert C, Dejager L, Pinheiro I. The X chromosome in immune
functions: when a chromosome makes the difference. Nat Rev
Immunol. 2010;10:594–604.
6. Fish EN. The X-files in immunity: sex-based differences predis-
pose immune responses. Nat Rev Immunol. 2008;8:737–44.
7. Pinheiro I, Dejager L, Libert C. X-chromosome-located microRNAs
in immunity: might they explain male/female differences? The
X chromosome-genomic context may affect X-located miRNAs
and downstream signaling, thereby contributing to the enhanced
immune response of females. BioEssays. 2011;33:791–802.
8. Hewagama A, Gorelik G, Patel D, Liyanarachchi P, McCune
WJ, Somers E, et al. Overexpression of X-linked genes in T cells
from women with lupus. J Autoimmun. 2013;41:60–71.
9. Brooks EG, Schmalstieg FC, Wirt DP, Rosenblatt HM, Adkins
LT, Lookingbill DP, et al. A novel X-linked combined immuno-
deficiency disease. J Clin Invest. 1990;86:1623–31.
10. Schmalstieg FC, Goldman AS. Immune consequences of muta-
tions in the human common gamma-chain gene. Mol Genet
Metab. 2002;76:163–71.
11. van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations
in FOXP3. Clin Dev Immunol. 2007;2007:89017.
12. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hart-
man J, et al. Estrogen receptors: how do they signal and what are
their targets. Physiol Rev. 2007;87:905–31.
13. Castles CG, Oesterreich S, Hansen R, Fuqua SA. Auto-regula-
tion of the estrogen receptor promoter. J Steroid Biochem Mol
Biol. 1997;62:155–63.
14. Shim GJ, Kis LL, Warner M, Gustafsson JA. Autoimmune glo-
merulonephritis with spontaneous formation of splenic germinal
centers in mice lacking the estrogen receptor alpha gene. Proc
Natl Acad Sci USA. 2004;101:1720–4.
15. Shim GJ, Wang L, Andersson S, Nagy N, Kis LL, Zhang Q,
et al. Disruption of the estrogen receptor beta gene in mice
causes myeloproliferative disease resembling chronic myeloid
leukemia with lymphoid blast crisis. Proc Natl Acad Sci USA.
2003;100:6694–9.
16. Lambert KC, Curran EM, Judy BM, Milligan GN, Lubahn DB,
Estes DM. Estrogen receptor alpha (ERalpha) deficiency in
macrophages results in increased stimulation of CD4+ T cells
while 17beta-estradiol acts through ERalpha to increase IL-4
and GATA-3 expression in CD4+ T cells independent of antigen
presentation. J Immunol. 2005;175:5716–23.
Sex differences in immune responses to infectious…
1 3
17. Gourdy P, Araujo LM, Zhu R, Garmy-Susini B, Diem S, Laurell
H, et al. Relevance of sexual dimorphism to regulatory T cells:
estradiol promotes IFN-gamma production by invariant natural
killer T cells. Blood. 2005;105:2415–20.
18. Angele MK, Schwacha MG, Ayala A, Chaudry IH. Effect of gen-
der and sex hormones on immune responses following shock.
Shock. 2000;14:81–90.
19. Sader MA, McGrath KC, Hill MD, Bradstock KF, Jimenez
M, Handelsman DJ, et al. Androgen receptor gene expression
in leucocytes is hormonally regulated: implications for gen-
der differences in disease pathogenesis. Clin Endocrinol (Oxf).
2005;62:56–63.
20. Medina KL, Garrett KP, Thompson LF, Rossi MI, Payne KJ,
Kincade PW. Identification of very early lymphoid precursors
in bone marrow and their regulation by estrogen. Nat Immunol.
2001;2:718–24.
21. Desquilbet L, Goujard C, Rouzioux C, Sinet M, Deveau C, Chaix
ML, et al. Does transient HAART during primary HIV-1 infec-
tion lower the virological set-point? AIDS. 2004;18:2361–9.
22. Moore AL, Kirk O, Johnson AM, Katlama C, Blaxhult A,
Dietrich M, et al. Virologic, immunologic, and clinical response
to highly active antiretroviral therapy: the gender issue revisited.
J Acquir Immune Defic Syndr. 2003;32:452–61.
23. Collazos J, Asensi V, Cartón JA. Sex differences in the clini-
cal, immunological and virological parameters of HIV-infected
patients treated with HAART. AIDS. 2007;21:835–43.
24. Farzadegan H, Hoover DR, Astemborski J, Lyles CM, Margolick
JB, Markham RB, et al. Sex differences in HIV-1 viral load and
progression to AIDS. Lancet. 1998;352:1510–4.
25. Sterling TR. When should highly active antiretroviral therapy be
initiated? Hopkins HIV Rep. 2001;13:11.
26. Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni
S, et al. Sex differences in the Toll-like receptor-mediated
response of plasmacytoid dendritic cells to HIV-1. Nat Med.
2009;15:955–9.
27. Herbeuval JP, Grivel JC, Boasso A, Hardy AW, Chougnet C,
Dolan MJ, et al. CD4+ T-cell death induced by infectious and
noninfectious HIV-1: role of type 1 interferon-dependent,
TRAIL/DR5-mediated apoptosis. Blood. 2005;106:3524–31.
28. Sodora DL, Gettie A, Miller CJ, Marx PA. Vaginal transmis-
sion of SIV: assessing infectivity and hormonal influences in
macaques inoculated with cell-free and cell-associated viral
stocks. AIDS Res Hum Retroviruses. 1998;14:S119–23.
29. Grebely J, Page K, Sacks-Davis R, van der Loeff MS, Rice TM,
Bruneau J, et al. The effects of female sex, viral genotype, and
IL28B genotype on spontaneous clearance of acute hepatitis C
virus infection. Hepatology. 2014;59:109–20.
30. Rodríguez-Torres M, Ríos-Bedoya CF, Rodríguez-Orengo J,
Fernández-Carbia A, Marxuach-Cuétara AM, López-Torres A,
et al. Progression to cirrhosis in Latinos with chronic hepatitis C:
differences in Puerto Ricans with and without human immuno-
deficiency virus coinfection and along gender. J Clin Gastroen-
terol. 2006;40:358–66.
31. Di Martino V, Lebray P, Myers RP, Pannier E, Paradis V, Char-
lotte F, et al. Progression of liver fibrosis in women infected with
hepatitis C: long-term benefit of estrogen exposure. Hepatology.
2004;40:1426–33.
32. McClelland EE, Smith JM. Gender specific differences in the
immune response to infection. Archivum Immunologiae et Ther-
apiae Experimentalis. 2011;59:203–13.
33. Narasimhan P, Wood J, Macintyre CR, Mathai D. Risk factors
for tuberculosis. Pulm Med. 2013;2013:828939.
34. Guerra-Silveira F, Abad-Franch F. Sex bias in infectious disease
epidemiology: patterns and processes. PLoS one. 2013;8:e62390.
35. Frieden TR, Lerner BH, Rutherford BR. Lessons from the
1800s: tuberculosis control in the new millennium. Lancet.
2000;355:1088–92.
36. Clarke WG, Cochrane AL, Miall WE. Results of a chest x-ray
survey in the Vale of Glamorgan; a study of an agricultural com-
munity. Tubercle. 1956;37:417–25.
37. Yamamoto Y, Saito H, Setogawa T, Tomioka H. Sex differences
in host resistance to Mycobacterium marinum infection in mice.
Infect Immun. 1991;59:4089–96.
38. Svanberg L. Effects of estrogen deficiency in women castrated
when young. Acta Obstet Gynecol Scand Suppl. 1981;106:11–5.
39. Curtis J, Turk JL. Resistance to subcutaneous infection with
Mycobacterium lepraemurium is controlled by more than one
gene. Infect Immun. 1984;43:925–30.
40. Demkow U, Filewska M, Michalowska-Mitczuk D, Kus J, Jag-
odzinski J, Zielonka T, et al. Heterogeneity of antibody response
to myobacterial antigens in different clinical manifestations of
pulmonary tuberculosis. J Physiol Pharmacol. 2007;58:117–27.
41. Pope V, Larsen SA, Rice RJ, Goforth SN, Parham CE, Fears
MB. Flow cytometric analysis of peripheral blood lymphocyte
immunophenotypes in persons infected with Treponema palli-
dum. Clin Diagn Lab Immunol. 1994;1:121–4.
42. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P,
Becker L, et al. Gender bias in autoimmunity is influenced by
microbiota. Immunity. 2013;39:400–12.
43. Bernin H, Lotter H. Sex bias in the outcome of human tropical
infectious diseases: influence of steroid hormones. J Infect Dis.
2014;209:S107–13.
44. Petrin D, Delgaty K, Bhatt R, Garber G. Clinical and microbio-
logical aspects of Trichomonas vaginalis. Clin Microbiol Rev.
1998;11:300–17.
45. Liesenfeld O, Nguyen TA, Pharke C, Suzuki Y. Importance of
gender and sex hormones in regulation of susceptibility of the
small intestine to peroral infection with Toxoplasma gondii tis-
sue cysts. J Parasitol. 2001;87:1491–3.
46. Karami M, Doudi M, Setorki M. Assessing epidemiology of
cutaneous leishmaniasis in Isfahan, Iran. J Vector Borne Dis.
2013;50:30–7.
47. Satoskar A, Alexander J. Sex-determined susceptibility and
differential IFN-gamma and TNF-alpha mRNA expression in
DBA/2 mice infected with Leishmania mexicana. Immunology.
1995;84:1–4.
48. Brabin L, Brabin BJ. Parasitic infections in women and their
consequences. Adv Parasitol. 1992;31:1–81.
49. Degu G, Mengistu G, Jones J. Some factors affecting preva-
lence of and immune responses to Schistosoma mansoni in
schoolchildren in Gorgora, northwest Ethiopia. Ethiop Med J.
2002;40:345–52.
50. Travi BL, Osorio Y, Melby PC, Chandrasekar B, Arteaga L, Sar-
avia NG. Gender is a major determinant of the clinical evolution
and immune response in hamsters infected with Leishmania spp.
Infect Immun. 2002;70:2288–96.
51. Lezama-Dávila CM, Isaac-Márquez AP, Barbi J, Oghumu S,
Satoskar AR. 17Beta-estradiol increases Leishmania mexicana
killing in macrophages from DBA/2 mice by enhancing produc-
tion of nitric oxide but not pro-inflammatory cytokines. Am J
Trop Med Hyg. 2007;76:1125–7.
52. Clayton JA, Collins FS. Policy: NIH to balance sex in cell and
animal studies. Nature. 2014;509:282–3.
