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Sex Drives Dimorphic Immune Responses to
Soumitra Ghosh and Robyn S. Klein
2017; 198:1782-1790; ;J Immunol
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Sex Drives Dimorphic Immune Responses to
Soumitra Ghosh* and Robyn S. Klein*
New attention to sexual dimorphism in normal mam-
malian physiology and disease has uncovered a previ-
ously unappreciated breadth of mechanisms by which
females and males differentially exhibit quantitative
phenotypes. Thus, in addition to the established mod-
ifying effects of hormones, which prenatally and post-
pubertally pattern cells and tissues in a sexually
dimorphic fashion, sex differences are caused by extra-
gonadal and dosage effects of genes encoded on sex chro-
mosomes. Sex differences in immune responses,
especially during autoimmunity, have been studied pre-
dominantly within the context of sex hormone effects.
More recently, immune response genes have been local-
ized to sex chromosomes themselves or found to be reg-
ulated by sex chromosome genes. Thus, understanding
how sex impacts immunity requires the elucidation of
complex interactions among sex hormones, sex chromo-
somes, and immune response genes. In this Brief Re-
view, we discuss current knowledge and new insights
into these intricate relationships in the context of viral
infections. The Journal of Immunology, 2017, 198:
Age, sex, and immune state of the host are considered
salient biological factors that determine the extent
and strength of pathogen clearance during infectious
diseases (1–3). With regard to viral infections, epidemiolog-
ical studies revealed that males have a higher mortality com-
pared with females, who reportedly display stronger antiviral
cellular and humoral immune responses (4). Although
stronger immune responses may provide better protection
against certain pathogens, in some chronic viral infections it
can lead to aberrant antigenic responses with immunopa-
thology (5, 6). Net sex differences or the degree of sexual
dimorphism in biological responses derive from genetic dif-
ferences in chromosome complement and induce their effects
via acute activational or prenatal organizational/epigenetic
effects of gonadal sex hormones (estrogen, progesterone, and
androgens), extragonadal effects of sex chromosome–encoded
genes, and compensatory mechanisms, such as reduction in
gene-dosage differences through X-chromosome inactivation.
These processes underlie sex differences in most tissue re-
sponses during normal and disease states, including immu-
nological responses to infectious diseases (Fig. 1).
Differences in susceptibility and response to viral pathogens
observed in males and females have primarily been attributed
to activational effects of sex hormones and dosages of genes on
the X and Y chromosomes (4). The onset of puberty is as-
sociated with the numbers and functions of circulating
granulocytes and monocytes, which are decreased, but acti-
vated, in females as a result of rising levels of progesterone in
the setting of ovulation or pregnancy (7, 8). In addition,
myeloid cells and lymphocytes express receptors for estrogen,
progesterone, and androgens, which orchestrate transcrip-
tional pathways and ligand-dependent or ligand-independent
signaling cascades that inﬂuence innate and adaptive immune
responses to viruses (9–12). With regard to gene dosage on sex
chromosomes, X-linked genes, such as IL-13,IL-4,IL-10,
XIST,TLR7,FOXP3, and sex-determining region Y box 9
(SOX9), on the X chromosome and sex-determining region Y
(SRY; testis-determining factor) and SOX9 on Y chromosome
may underlie sexually dimorphic responses that contribute to
stronger innate, cellular, and humoral immune responses and
susceptibility to autoimmune diseases in females compared
with males (13–15). Studies in humans and animal models
indicate sexually dimorphic mechanisms that contribute to
virologic control during infections with HIV-1, vesicular
stomatitis virus, hantavirus (Seoul virus), inﬂuenza virus
(H1N1), hepatitis C virus, Theiler’s murine encephalomy-
elitis virus, HSV-1 and coxsackievirus B3 (CVB3) (5, 16–20).
In this review, we introduce the various mechanisms that
impose sexual dimorphism in immune function in males and
females. We then discuss the impact of sexually dimorphic
immune responses on pathogenesis during viral infections.
Organizational effects of sex hormones on immune function
The initiation of sexual dimorphism occurs through early
embryonic development due to effects of genes on sex chro-
mosomes (21, 22). The SRY gene on the Y chromosome
*Department of Internal Medicine, Washington University School of Medicine,
St. Lo uis , MO 63110;
Department of Pathology and Immunology, Washington Uni-
versity School of Medicine, St. Louis, MO 63110; and
Department of Neuroscience,
Washington University School of Medicine, St. Louis, MO 63110
ORCID: 0000-0001-6785-6362 (S.G.).
Received for publication July 5, 2016. Accepted for publication October 24, 2016.
This work was supported by National Institutes of Health Grants R01 NS052632 and
U19 AI083019 and a grant from the National Multiple Sclerosis Society (all to R.S.K.).
Address correspondence and reprint requests to Dr. Robyn S. Klein, Department of
Medicine, Washington University School of Medicine, 660 South Euclid Avenue,
St. Louis, MO 63110. E-mail address: email@example.com
Abbreviations used in this article: AR, androgen receptor; CVB3, coxsackievirus B3; E2,
17b-estradiol; E3, estriol; ER, estrogen receptor; FCG, four-core genotype; MCMV,
murine CMV; pDC, plasmacytoid dendritic cell; RSPO, R-spondin; SLE, systemic
lupus erythematosus; SOX9, sex-determining region Y box 9; SRY, sex-determining
region Y; Treg, regulatory T cell.
Copyright Ó2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00
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induces male supporting cell precursors to differentiate into
testosterone-expressing Sertoli cells, leading to masculiniza-
tion of all tissues within the developing embryo (23–25).
During embryonic development, the increased expression of
multiple genes maintains the XX sex phenotype and inhibits
the expression of genes, such as SOX9, a transcription factor
that favors the XY male phenotype (15). In males, expression
of SOX9 protein downstream of Sry is crucial in inducing
male sex phenotype. SOX9 can independently induce male-
to-female sex reversal in male embryos through deletion from
chromosome 17 (23, 26, 27). Gonadal R-spondin (RSPO)1 is
a secreted protein that is highly expressed in female blastocysts
and interacts with Wnt4, which promotes ovarian develop-
ment and estrogen production via the Wnt4/b-catenin sig-
naling pathway (28, 29). Loss-of-function mutational studies
in RSPO1 and RSPO
XX mice conﬁrmed this observa-
tion (27–30). FOXL2, a forkhead transcriptional regulator,
also contributes to ovarian differentiation and maintenance
during embryonic development in females via suppression of
testis-speciﬁc or male sex–determining genes, such as SRY
target gene SOX9 and ﬁbroblast growth factor 9, the latter of
which represses Wnt4 (31–34). Although SOX9 deletion is
embryonically lethal, homozygous conditional inactivation
and mutational studies of SOX9 conﬁrmed that SOX9 in-
duces suppression of Wnt4, Foxl2, and b-catenin to prevent
feminization of the male embryo (15). In addition, SOX9
increases the expression of genes required for male phenotype
development in mammals, including steroidogenic factor1,
doublesex and mab-3 related transcription factor 1, and GATA4-
binding protein (23, 31, 35, 36).
Studies in rodents show that sexual dimorphism in immune
function occurs through embryonic development and is
maintained postnatally via the actions of gonadal hormones,
such as estrogen and testosterone (37–39). Prenatal castration
of male mice results in postpubertal thymic involution and
aberrant T cell subset differentiation (40). Females exposed to
higher concentrations of androgen prenatally as a result of
congenital adrenal hyperplasia exhibit less modeling of be-
havior shown to them by other females, suggesting that
gender-related behavior change is due to prenatal hormonal
exposure (41). Surprisingly, immune response to heterologous
MLR (MLR-A) is unaffected by perinatal masculinization in
both sexes and is strongest in unmanipulated females (42, 43).
Consistent with this, loss of feminization at prenatal stages
leads to decreased T cell/B cell ratios compared with normally
feminized mice, whose ratios mirror those observed in male
animals (44). Several studies also report the role of gonadotropin-
releasing hormone, which maintains early levels of gonadal hor-
mones in both sexes, in the prenatal patterning of the immune
system. Postnatal gonadotropin-releasing hormone antagonism,
which inhibits expression of gonadal hormones, results in lower
numbers of circulating CD8
T and B cells in male rodents and
primates (45). Similar studies in female rats showed reduced
numbers of CD4
T cells and reduced immune responses of
thymocytes and splenocytes to T cell–mediated Ag (46, 47). The
effects of estrogen and testosterone on B cell development and
differentiation also directly inﬂuence the production of IgG (48,
49). Prenatal secretion of testosterone limits the ability of males to
produce Igs compared with females, who maintain much higher
default plasma anti-DNA Ig levels compared with males (2, 50).
Additional studies in seagull chicks reveal a reduced T cell and
plasma Ig–mediated immunity in prenatal testosterone-treated
chicks compared with control chicks (51). Activational effects
of hormones at puberty further enhance sex differences in Ab
production that are present at birth (see below), leading to per-
sistently higher humoral immune response in females throughout
Activational effects of hormones on immune function
Postpubertal expression of gonadal hormones leads to acute
and reversible effects in adulthood that maintain physical and
behavioral sex differences (52). Estrogen and progesterone in
females and testosterone in males are the prime gonadal
hormones secreted during the activational period. The effect
of hormonal secretion during this period is not limited to the
reproductive system; it extends to multiple tissues, including
those of the immune system (53). The androgen testosterone
is synthesized in gonadal and adrenal tissues of males and
females but is predominantly converted to estrogens via aroma-
tization in the latter (54). Endogenous estrogens produced in
female mammals include estrone, 17b-estradiol (E2), and
estriol (E3). E2 is the predominant form in females and is
produced by theca and granulosa cells of the ovaries in pre-
menopausal women. The level of hormones secreted in post-
pubertal female mammals varies in a cyclic fashion to facilitate
ovulation and subsequent pregnancy.
Estrogen receptors (ERs) exist in two forms, ERaand ERb,
which bind estrone, E2, and E3 ligands to mediate gene expres-
sion. B and T lymphocytes, mast cells, macrophages, dendritic
cells, and NK cells predominantly express ERa(55). Hema-
topoietic progenitor cells express ERaand ERb(56). Based
FIGURE 1. Mechanisms of tissue sexual dimorphism that underlie sex dif-
ferences in immune responses. Sex hormones, such as estrogens and androgens,
contribute to organizational and activational effects via gene effects that include
promoter activation and chromatin remodeling (epigenetic modiﬁcations). Sex
chromosome complement exerts its effect in promoting sexual dimorphism
independent of sex hormones. X-dosage compensation and escape from X-in-
activation inﬂuence differential gene expression of innate immune molecules. Y
chromosome contributions include Y gene–associated polymorphisms. Studies
evaluating sexual dimorphism in immune responses focus on the interdepen-
dence of these factors, as well as their independent contributions.
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on studies in ERa-andERb-deﬁcient mice, ERaappears to
be the key regulator in the differentiation of hematopoietic
progenitor cells (57). Females produce higher levels of estro-
gen and regulate ER activation on their immune cells, which
helps them to exert a stronger humoral and cellular immune
response (37, 58).
ERs play vital roles in several signaling pathways, acting as a
signal transduction molecule in calcium regulation across cell
membranes and inducing activation of G coupled– and other
surface receptors, such as receptors that drive expression of
insulin growth factor 1 and activation of ERK/MAPK, pro-
tein kinase C, PI3K, and cAMP signaling (59, 60). ERais
also required for proper dendritic cell differentiation and
CD40-mediated cytokine production (61). Although ERs can im-
pact signaling pathways in ligand-dependent and -independent
manners (62), signaling in immune cells is ligand-dependent,
whereas signaling through coactivator-associated arginine methyl-
transferase 1 is ligand independent. E2 receptor [speciﬁcally
ERa46 (63)] mediates anti-inﬂammatory signaling in mono-
cytes and macrophages through suppression of CXCL8 (63,
64). ERs activate STAT signaling pathways during T and B cell
proliferation, maintenance, and activation. Under inﬂammatory
conditions, ER activation also induces NO synthase and IFN-g
expression in T cells. ER ligands also mediate phosphorylation,
nuclear localization, and transcriptional activation of STAT1,
STAT3, and STAT5 in B cells and circulating monocytes (65,
66). E2 additionally regulates STAT activity by increasing
expression of cytokine-inhibitor proteins, such as suppressor
of cytokine signaling 1 and 5, in T cells and macrophages
(67–70). In macrophages, ER signaling mediates inhibitory
responses toward proinﬂammatory genes regulated by NF-kB,
such as IL-6. In contrast, E2 directly suppresses the expression
of CCL2 in leukocytes, leading to a reduction in migration
It is well established that ERs play an important role in
promoting sexual dimorphism in the neonatal brain through
chromatin remodeling, particularly via promoter methylation
and acetylation. This process is mediated by ERaactivation
and dimerization, followed by nuclear translocation, DNA
binding through estrogen-response elements, and recruitment
of receptor coactivators and corepressors, such as nuclear re-
ceptor corepressors, leading to epigenetic modiﬁcations and
regulation of downstream transcriptional factors (73–75).
Current studies on epigenetics also indicate that methylation
of the ERapromoter contributes to sex differences in the
brain, as well as maintains sexual dimorphism throughout life
by creating methyl marks on the DNA of the individual (76).
However, direct evidence for ER- or androgen receptor (AR)-
mediated epigenetic modiﬁcations that contribute to immune
cell differentiation and function has not been found.
In addition to endogenous ER ligands, ligands that effect ER
signaling are found in environmental sources, including food
(e.g., phytoestrogens) and pharmaceuticals (e.g., tamoxifen,
toremifene and raloxifene, which are selective ER modulators).
Selective ER modulators have been used as therapeutics in
multiple sclerosis, ovarian cancer, breast cancer, and Ebola
virus infection to suppress the activity of Th1 cells and induce
Th2 cytokine expression (77–81). Further studies are required
to understand the impact of environmental and exogenous
estrogens, either independently or in combination with other
factors, on immune function during exposure to pathogens.
Progesterone also mediates stimulatory and suppressive roles
in immune responses. Progesterone receptors are primarily
expressed by T and NK cells, but recent studies detected them
on dendritic and mesenchymal stem cells, where they suppress
Th1 cytokine secretion and increase Th2 cytokine secretion
(82, 83). Suppression of T cell cytotoxicity, as well as regu-
latory T cell (Treg) proliferation, is also mediated by pro-
gesterone (84). Progesterone also inhibits the activity of NK
cells via downregulation of IFN-gsecretion (85). In macro-
phages, progesterone suppresses NO levels and inhibits FcgR
expression and microparticle release, thereby dampening the
initial immune response at initial stages of infection. During
pregnancy, progesterone enhances immunomodulatory func-
tions of mesenchymal stem cells through upregulation of
PGE-2 and IL-6. This is essential in females to maintain the
fetal–maternal interface (83).
Most testosterone (98%) is irreversibly converted to an
active metabolite, dihydrotestosterone (86), which binds with
higher afﬁnity than testosterone to ARs, which are expressed
at various levels by leukocytes (87). In innate immune cells,
such as neutrophils, AR signaling maintains cellular differ-
entiation via induction of G-CSF signaling through activation
of ERK1/2 and STAT3 (88). In wound-healing studies, AR
regulates the chemotactic ability of macrophages through
upregulation of CCL2, TNF-a, and CCR2 (89). AR signal-
ing also regulates T and B cell function and development.
thymocytes express lower levels of inducible AR,
thymocytes express the
highest levels (90). Although AR signaling promotes Th1-
mediated T cell immune response, it also acts as an antago-
nist to NF-kB and IFN type I signaling pathways (91).
Speciﬁcally, splenic CD4
T cells express inducible
AR that binds to testosterone in males (92). Castration studies
revealed that, in the absence of testosterone, AR signaling
suppresses the activation of CD4
T cells via
overproduction of IL-2 and IL-2R (47, 93). Moreover, the
absence of testosterone leads to dampening of Th1 differen-
tiation from naive CD4 T cells in autoimmune disease con-
ditions through suppression of IFN-gand IL-2 expression in
males (94, 95).
Sex chromosome complement and immune function
Sex chromosome complement arises from fundamental genetic
differences in XX and XY cells that are mediated by several
processes, such as X chromosome inactivation, X gene dosage,
and epigenetic modiﬁcations (96). To maintain X gene dosage
in the female blastocyst, one of the X chromosomes is inac-
tivated by formation of Barr bodies in individual cells (97).
Barr bodies are formed as a result of Xist gene expression and
histone modiﬁcation, making one of the X chromosomes
inactive in every cell (98). This process, which is exclusive to
XX somatic cells, is random and leads to cells with active
maternal or paternal X and compensates X gene dosages in all
somatic cells (14). The gene products of X or Y gene also
facilitate epigenetic modiﬁcations on the DNA of an indi-
vidual. SRY interacts with Kruppel-associated box domain
transcriptional factor through the high mobility group box on
SRY to recruit histone-modifying enzymes, such as histone
deacetylase and heterochromatin protein 1, which remodels
chromatin (99, 100). Few studies evaluated sexual dimor-
phism in chromatin remodeling, irrespective of hormonal
1784 BRIEF REVIEWS: SEX DIFFERENCES IN VIRAL INFECTIONS
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inﬂuence, and those that did focused on the CNS. Thus, H3
methylation is more prevalent in cortical regions of the brain
in males compared with females (101), and histone deacety-
lase 2 and 4 bound more prevalently to promoters of Esr1 and
Cyp19a during brain differentiation in males compared with
females. This increased interaction leads to stronger deacety-
lation and higher gene expression (102).
microRNAs are also sexually dimorphic in nature and
regulate SRY-related genes. For example, in the prenatal stage,
miR-124 is highly expressed in female-supporting cells and
suppresses SOX9 gene expression. In contrast, miR-202-5p/
3p is highly expressed in males through SOX9, which is
generated by male-supporting cells, and is necessary for male
sex determination. Data also suggest that miR-202-5p is a
direct transcriptional target of SOX9 during testis differenti-
ation (103). Interestingly, miR-124 also was shown to inhibit
STAT3 signaling, which suppresses T cell proliferation and
leads to Foxp3
Treg induction, including upregulation of
IL-2, IFN-g, and TNF-a(104, 105). Another study using a
murine model of multiple sclerosis found that peripheral
administration of miR-124 leads to systemic deactivation of
macrophages, reduced activation of myelin-speciﬁc T cells,
and suppression of disease progression (106). Because research
regarding the role of sex chromosome complement in many
physiologic and disease processes is still in its early stages, less
is known about their contributions to antiviral immunity.
However, studies using four-core genotype (FCG) mice, in
which the role of XX versus XY genes can be separated from
those of gonadal hormonal effects, are providing new insights
into the impact of sex chromosome complement on immune
responses, particularly during autoimmune diseases.
Female bias in disease expression of autoimmunity is well
established, with female/male ratios in systemic lupus ery-
thematosus (SLE) and multiple sclerosis approaching 4:1 and
9:1, respectively. A study of sex chromosome aneuploidy in
male subjects expressing an excess X chromosome found that
they were at a higher risk for SLE (107). Thus, the X chro-
mosome likely plays a crucial role in disease incidence inde-
pendently of hormonal effects (107, 108). The FCG mouse
model is a novel tool for examining the effect of sex chro-
mosome complement XX and XY on phenotypic sex differ-
ences induced in male and female mice without the
confounding effects of hormonal patterning. In the FCG
model, the testis-determining gene Sry is deleted from the Y
chromosome on male B6 or SJL mice (XY
), and a transgenic
Sry is inserted at multiple sites on an autosome (109). The
model generates four genotypes of mice; the Sry transgene is
present in XX and XY
mice, which develop testis in contrast
mice, which develop ovaries similar to XX mice (109).
Gonadectomy of FCG mice allows further examination of the
genetic contributions of sex chromosomes in adult animals
that do not express sex steroids.
Using FCG mice, XXSry mice were found to display in-
creased susceptibility for SLE and experimental autoimmune
encephalomyelitis compared with XY
Sry mice. Because both
XXSry and XY
Sry mice had testes during development, and
the only difference between the two groups is the presence of
the Y chromosome complement, this study conﬁrmed that sex
complement alone could promote susceptibility to diseases,
irrespective of the hormonal secretions (52, 108). Further
comparison between XX and XY
mice found higher levels of
IL-13Ra2 and reduced levels of Th2 cytokines in spleen cells
isolated from XX mice. These results suggest that subdued
Th2 cytokine levels that result from an increase in X linked
gene IL-13Ra2 expression could be due to X chromosome
Sexually dimorphic immunity to viral infections
Differences in susceptibility to viral infections are likely due to
inherent differences in the immune system of females and
males. Females mount a stronger immune response to viral
infections compared with males as the result of more robust
humoral and cellular immune responses (Fig. 2). Clinical
studies of viral infections in humans are complicated by the
impact of nonbiological factors, such as exposure rates, social
behavior, habitat and diet, on viral pathogenesis in a sex-
speciﬁc fashion. However, studies in a controlled setting
suggested that levels of estrogen and testosterone differentially
alter the expression of genes involved in innate immunity,
such as those encoding TLRs and IFNs, in females and males,
thereby contributing to sexual dimorphism in viral infections.
Immune response to viral infections
The innate immune response is the ﬁrst line of defense against
any viral infection. Males and females exhibit a different
pattern of response to viral infections. The innate response is
primarily mediated by three classes of pattern recognition
receptors (PRRs): TLRs, retinoic acid–inducible gene I–like
receptors, and nucleotide oligomerization domain–like re-
ceptors (110, 111). These PRRs detect viral components, such
as genomic DNA, dsRNA, ssRNA, RNA with 59-triphos-
phate ends, and viral proteins. TLRs and retinoic acid–
inducible gene I–like receptors speciﬁcally regulate the
production of type 1 IFNs and other cytokines. In contrast,
nucleotide oligomerization domain–like receptors regulate
FIGURE 2. The interplay of sex chromosomes, sex hormones, and immune
responses inﬂuence sex differences in virologic control. Females display in-
creased innate and adaptive immune responses to most viral infections
compared with males as a result of differences in the effects of sex hormones
(estrogen, progesterone, and androgen). X and Y chromosome complement
also contribute to sexually dimorphic immune responses to viruses in females
and males. The relative increase in immune responses in females may con-
tribute to differential levels of virologic control during acute infections and/or
immunopathologic effects of antiviral T cells that may lead to chronic
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IL-1bthrough caspase-1 activation (110, 112, 113). Sexual
dimorphism is observed during antiviral responses mediated
by TLR and IFN pathways (114, 115). Immune cells in
females exhibit a 10-fold higher expression of TLRs com-
pared with males (116). In mammals, the number and ac-
tivity of innate immune cells, such as monocytes, macrophages,
and dendritic cells, are higher in females than in males. As a
result, responses to Ags, vaccines, and infections are also higher
in females compared with males (3, 117). The adaptive im-
mune response also exhibits many sexual differences in response
to viral infections. Depending on the stage of the infection,
females exhibit higher inﬂammatory Th1 and anti-inﬂammatory
Th2 compared with males (3). Additionally, upregulation of
anti-inﬂammatory genes and higher cytotoxic T cell activity are
observed in females. Some studies also showed higher numbers
of Tregs in females compared with males. Clinical investiga-
tions in humans also reported lower instances of CD3
ratios in Th cells in males compared with
females (44, 118).
DNA virus members of the Herpesviridae family
Like many DNA viruses, herpesviruses replicate within host
cell nuclei, with their genome persisting as an episome for the
life of the host. In this study we will discuss sexually dimorphic
responses to herpesvirus infections that have been traced to
activational effects of gonadal hormones.
HSV-1 and HSV-2. Infection with HSVs, DNA viruses that
cause oral and genital herpes, and rare encephalitis in im-
munocompetent individuals can lead to devastating disease in
neonates and immunocompromised patients via extensive
dissemination to visceral organs and the CNS (119). In males,
the T cell–suppressive effects of androgens appear to protect
against inﬂammatory-mediated demyelination infected with
HSV-1 (120). Studies in mice showed that E2 treatment
increases the chances of survival and decreases vaginal pathol-
ogy and inﬂammation in HSV-1–infected females (121).
Consistent with this, females infected with HSV generate
higher levels of HSV-speciﬁc IgG and IgM compared with
males (122). Similarly, females infected with HSV-2 are
protected against neurologic damage and viral reactivation
via virus-speciﬁc CD8
T cell activation (123, 124). Studies
in ovariectomized mouse models indicated that progesterone
treatment increases the susceptibility of females to genital HSV-2
infection, whereas estrogen treatment helps to clear the infection
rapidly. Interestingly, combined treatment with estrogen and pro-
gesterone in ovariectomized mice resulted in increased infection
spread that was accompanied by persistent inﬂammation and
neutrophil inﬁltration (125, 126). Although studies do not
directly indicate the organizational effect, the effect of estrogen
and progesterone in ovariectomized animals suggests an effect of
sex hormones in HSV-2 infection.
CMV and murine CMV. CMV, a member of the Herpesviridae
family with a large genome, causes systemic viral infections
in immunocompetent individuals that may be devastating
and life-threatening in the immunocompromised (127).
Knowledge of sexual dimorphism in CMV infection stems
from experiments in murine CMV (MCMV), which is
genetically similar to CMV and has been used to study the
pathogenesis of CMV in mouse models. In MCMV-infected
female mice, IFN-a/bproduction by splenic plasmacytoid
dendritic cells (pDCs) controls viral replication and is required
to prevent viral reactivation (128). Studies in MyD88
infected with MCMV showed suppression of TLR9 signaling in
neutrophils of female mice, which wasassociatedwithincreased
viral replication (129). Additionally, CD4
responses, including expression of TNF-a, IL-12, IL-6, and
IFN-g, which are required for clearance of CMV, are also
mediated primarily by TLR9 signaling, which is decreased in
females (130, 131).
RNA viruses may replicate in either the nucleus or the cytoplasm
and, except for HIV-1, are generally cleared by host adaptive
immune responses. In this article we outline sexually dimorphic
immune responses to clinically relevant RNA viruses.
Hantavirus. Hantavirus is a negative-sense RNA virus of the
Bunyaviridae family that predominantly infects rodents.
Airborne transmission of virus occurs in humans by exposure
to rodent urine, feces, and saliva and leads to hantavirus
pulmonary syndrome, a severe respiratory disease that may be
fatal (132). Male rats infected with the Seoul virus strain
exhibit higher viral burdens in target organs and shed virus
for a longer duration than do similarly infected female
animals (16, 133, 134). Accordingly, antiviral and proinﬂammatory
factors, such as Tlr7,MyD88,Ifn-b,TNF-a,andCcl5, are more
highly expressed in female rodents (16, 135). Consistent with
this, acute infection with Puumala virus strain in humans is
associated with higher concentrations of IL-9 and GM-CSF
in females compared with males (136, 137).
CVB3. Coxsackieviruses (genus Enterovirus) belong to the
Picornaviridae family of positive-sense ssRNA viruses. CVB3
infection leads to myocarditis during the acute and chronic
phases, which affects more males than females, with double
the mortality in infected individuals under the age of 40
(138). Cardiomyocytes are directly infected by CVB3 during
the acute phase, which is followed by a chronic phase with a
prolonged T cell–mediated immune response and persistence of
CVB3 within the heart (139). Coxsackievirus AR is required for
CVB3 entry into cardiomyocytes (140). Chronic-phase CVB3
myocarditis is an autoimmune disease that requires Th17 cells
and whose differentiation and expression of IL-17 are suppressed
by estrogen, making females less susceptible (138, 141). In
contrast, lack of estrogen and the presence of testosterone
induce Th17 cell differentiation in CVB3-infected males,
enhancing autoimmune-mediated cardiac damage. In females,
Th2- and Treg-mediated immune responses, which are
increased through ERasignaling in T cells and macrophages
in heart tissues, suppress CVB3-mediated immunopathology
while clearing infection (139, 142). A recent study also
indicates that sex chromosome complement plays a signiﬁcant
role in survival from CVB3 infection. Survival of CVB3-infected
B6-ChrY consomic male mice was exclusively dependent on the
loci on chromosome Y and independent of prenatal or
adult testosterone (24). In summary, the immune make-up of
the males and the presence of male sex steroid testosterone
promote the spread of CVB3, leading to myocarditis. Sex
complement, as well as the activational effect of hormones,
contributes to CVB3 pathogenesis.
Inﬂuenza. The incidences of H5N1 avian inﬂuenza and H1N1
and H2N2 pandemic inﬂuenza, RNA viruses that cause severe,
inﬂammatory-induced respiratory diseases, all demonstrate
1786 BRIEF REVIEWS: SEX DIFFERENCES IN VIRAL INFECTIONS
by guest on March 15, 2017http://www.jimmunol.org/Downloaded from
signiﬁcant sexual dimorphism, affecting more females than
males (143, 144). Reports on H1N1 pandemic inﬂuenza
indicated higher mortality in females of reproductive age
(20–49 y), implicating roles for female gonadal hormones,
especially during pregnancy (145). In murine studies,
H1N1 infection in female mice prolongs the diestrus cycle,
leading to lower serum levels of E2 (5, 145, 146). This
reduction in E2 signiﬁcantly increases the expression of
inﬂammatory cytokines and chemokines, including TNF-a,
IFN-g, IL-6, and CCL2, the latter of which promoted the
inﬂux of mononuclear cells into virally infected lungs and
exacerbated immune responses (5, 147). Under chronic
infection, low levels of E2 bind to ER-aand modulate
NF-kB transcriptional activity, further contributing to augmented
inﬂammatory responses and immunopathology (114, 145).
In contrast, lower levels of estrogen and higher levels of
androgen in inﬂuenza-infected males were linked to immuno-
suppression and reduced T cell counts, which may limit
immunopathology in males (148). Clearly, more studies
emphasizing the interplay among sex, hormones, and genes
are required to further understand the effect of sexual
dimorphism on inﬂuenza pathogenesis.
HIV-1. Untreated HIV-1 infection leads to AIDS, with near-
complete loss of CD4
T cells. Meta-analysis data show 41%
less HIV RNA in women compared with men following
primary infection, which gradually increase to a higher viral
load set point compared with males after chronic infection
(149–151). In females, HIV-1 promotes type 1 IFN production
by pDCs via TLR7 signaling, which itself is increased
downstream of E3 signaling (115, 152). These effects lead to
strong, initial cellular responses that limit HIV-1 replication
(153). However, continuous production of type 1 IFN by
pDCs in females leads to chronic T cell activation with CCR5
expression, providing more targets for HIV-1 (154). In HIV-1–
infected women, pDCs produce more IFN-athrough TLR7
ligand activation. This results in a secondary activation of
T cells (115). Follow-up studies showed that, even with
the same viral load, pDCs ob taine d fr om f emale s showed
T cell activation compared with men (115).
Additionally, females mount a stronger B and T cell activation
following HIV-1 infection as a result of the higher baseline
count of CD4
T and CD8
T cells compared with men
(115, 151). The concentration of estrogen-binding SHBG is
increased in HIV-infected males. Although the mechanism
is not well understood, suppressing SHBG levels decreases
the severity of HIV infection in male patients (155, 156).
Another recent study in SCID mice showed that ERs ESR1
and ESR2 and X chromosome complement in females are
necessary for IFN-aand TNF-aproduction under TLR7
activation in pDCs (157). This study conﬁrmed that
estrogen, female sex hormones, and X chromosome dosage
confer stronger innate and adaptive immune responses in
females compared with males in HIV infection. Altogether,
these studies suggest that estradiol treatment could facilitate a
stronger immune response to HIV infection.
Although sexual dimorphism is observed in HIV patho-
genesis, studies are needed to better understand the underlying
mechanisms that contribute to sex-based immune cell regu-
lation in HIV-1–infected patients. These will assist in the
design of experiments and the accuracy of clinical trials in
Vaccine for viral infections
A sexually dimorphic response to viral vaccines is observed in
males and females. Viral vaccines against hepatitis A, hepatitis
B, and HSV-2 all exhibit a stronger side effect in young females
following immunization. Higher IgA and IgG Ab responses, as
well as higher transcriptional activation of genes important in
immune cell signaling, such as IFN and TLR7, are also ob-
served in females compared with males (143, 158). These
studies clearly demonstrate that the development of vaccines
against viral infection should carefully consider the effect of
differential immune responses in males and females.
This review highlights early and recent ﬁndings regarding the
impact of sex on immune cell numbers and function, with a
focus on sexually dimorphic phenotypes during viral infec-
tions. Although still an emerging ﬁeld, it is clear that mech-
anisms by which mammals achieve and maintain sex
differences can directly and indirectly inﬂuence host–path-
ogen interactions at the cellular and molecular levels. These
ﬁndings support the notion that there are, in fact, “two
normals” with regard to manifestations of infectious diseases,
with sex-speciﬁc responses during acute virologic control and
in immunopathologic manifestations of viral infections.
Accordingly, the development of therapeutics to treat vari-
ousphasesofviralinfectionswill require continued study
and comparisons of viral pathogenesis in female and male
animals and humans.
The authors have no ﬁnancial conﬂicts of interest.
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