Gender influences the incidence and severity of some bacterial and
viral infections and autoimmune diseases in animal models and humans.
To determine a gender-based difference, comparisons were made between
male and female mice inoculated with herpes simplex virus type 1 (HSV-1) by the corneal route. Mortality was higher in the male mice of
the three strains tested: 129/Sv//Ev wild type, gamma interferon
(IFN-
) knockout (GKO), and IFN- receptor knockout (RGKO).
Similarly, in vivo HSV-1 reactivation occurred more commonly in male
mice, but the male-female difference in reactivation was restricted to
the two knockout strains and was not seen in the 129/Sv//Ev control.
Comparison among male mice of the three strains showed a higher
mortality of the RGKO mice and a higher reactivation rate of the GKO
and RGKO mice than of the 129/Sv//Ev males. In contrast, female RGKO
and GKO mice did not differ from female 129/Sv//Ev controls in either
mortality or reactivation. HSV-1 periocular and eyelid disease was also more severe in male and dihydrotestosterone (DHT)-treated female mice
than in control female mice. These results show a consistent gender
difference in HSV-1 infection, with a worse outcome in male mice. In
addition, the results comparing GKO and RGKO mice to controls show
differences only in male mice, suggesting that some effects of IFN-,
a key immunoregulatory molecule, are gender specific.
 |
TEXT |
It has long been appreciated that
males and females differ in susceptibility to a variety of infections
and diseases. Gender-determined differences in susceptibility to virus
infections have been reported for encephalomyocarditis virus
(8), vesicular stomatitis virus (3), and
coxsackievirus B3 (CVB3) (20). Females mount more vigorous
immune responses, especially humoral responses, and in general show
higher resistance to bacterial and viral infections (1, 3,
22). Females are also disproportionately afflicted by autoimmune
disease, such as lupus erythematosus, rheumatoid arthritis, myasthenia
gravis, scleroderma, Sjögren's syndrome, multiple sclerosis,
experimental allergic encephalomyelitis (EAE) (10, 28,
36), and herpes simplex virus (HSV). Despite early reports of
differences in antibody titer (22) and severity of paralysis after HSV-1 inoculation of mice (18, 38),
gender-based differences in HSV-1 infection or in HSV-1-associated
diseases have not been well studied.
The mechanisms underlying gender- or, strictly, sex-based differences
in susceptibility to infection and diseases remain ill defined
(3, 35, 36); however, several recent studies suggest that
differences in immune responses may involve gender. Gamma interferon
(IFN-), an important immunoregulatory cytokine, plays a key role in
the development of balanced Th1/Th2 responses that are essential for
efficient control of infectious intracellular pathogens. Th1-type
responses are generally regarded as more effective for controlling
viral infections, but excessive responses can have serious
immunopathological consequences (15, 16, 33). Indeed,
IFN- can be either protective or deleterious during infection with
HSV-1, depending on the target tissue (17). IFN- is
associated with damaging corneal lesions in herpetic stromal keratitis
but is required for control of cutaneous and reactivated HSV-1
infections. Although activity of the IFN- promoter is known to
increase by treatment of lymphoid cells with estrogen
(13), whether estrogen regulation occurs in vivo is
unknown. To determine possible gender-specific effects of IFN-, we
compared the outcomes of HSV-1 infection in male and female wild-type
mice (129/Sv//Ev) and mutant mice lacking either the IFN- gene
(IFN-
/) (GKO) (11) or the
IFN- receptor (IFN-R) gene (IFN-R/)
(RGKO) (19).
Gender effects on HSV-1 acute infection.
Male and female
mutant GKO and RGKO mice and wild-type mice, all in the 129/Sv//Ev
background (32), were used at 6 to 9 weeks of age for
these studies. Because GKO mice were only available in the C57BL/6
background, we introduced the IFN-/ null
mutation into the 129/Sv//Ev background by using an ES cell clone (97E)
heterozygous for the IFN- mutation as described previously (5). Male and female mice were housed in the same suite
under specific-pathogen-free conditions. 129/Sv//Ev mice used as
controls were obtained from a commercial supplier (Taconic, Inc.,
Germantown, N.Y.). To determine the effects of gender on mortality,
male and female 129/Sv//Ev mice were inoculated with HSV-1 by corneal
scarification as previously described (5), and mortality
at the acute stage of infection (up to 2 weeks after inoculation) was
recorded. As shown in Table 1, the rates
of mortality in 129/Sv//Ev mice were 23% in males and 8% in females
(P = 0.04). Since the IFN- promoter has been shown
to be regulated by estrogen (13), it is conceivable that
IFN- contributes to gender differences in infectious and inflammatory diseases. To determine if the HSV mortality difference noted in 129/Sv//Ev mice was similar in mice deficient in IFN-, we
reviewed mortality records in over seven experiments with the null
mutant RGKO and GKO mice (5; E. Cantin and J. Mann,
Letter, J. Immunol. 162:6294-6295, 1999). As shown in
Table 1, the mortality in female RGKO and GKO mice was 8% (the same
mortality as in the female 129/Sv//Ev controls), whereas the mortality
rates in both male null mutant mouse strains were significantly higher: 38% in RGKO mice (P = 0.0001) and 23% in GKO mice
(P = 0.0002). These differences correspond to a 3.4- to
5.4-higher risk of death for males in both RGKO and GKO mutant
and control mice. Viral titers determined in trigeminal ganglia and
brain stem tissue homogenates at the peak of the acute infection on day
4 showed no significant male-female differences (not shown). A time
course study monitoring HSV-1 titers in trigeminal ganglia of
129/Sv//Ev mice on days 4, 7, and 9 confirmed this result and further
showed that the kinetics of clearance of HSV-1 from the ganglion was also not affected by gender (Fig. 1).
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FIG. 1.
Time course of HSV-1 replication in the trigeminal
ganglion (Tg). Three mice per group were sacrificed at the indicated
times, and HSV-1 titers were determined in ganglionic homogenates by
plaque assay on CV-1 monolayers; titers are expressed as means ± standard errors.
|
|
The summary in Table 1 of mortality records from several experiments
permitted comparisons among the three mouse strains that revealed
interesting new findings. An analysis of only male mice showed a
significantly higher mortality in RGKO mice than in GKO mice
(P = 0.0001) or wild-type 129/Sv//Ev mice
(P = 0.04), as previously reported (5).
This result showing that the IFN-R, more than IFN- itself,
protects against mortality underpins speculation that in GKO mice
binding of alternative ligand to the IFN-R may mediate protection
(5). Interestingly, the action of this putative alternative ligand does not appear to affect female mice, since the
rates of mortality are the same in RGKO and GKO females. However, unlike GKO mice, male RGKO mice have a higher mortality than control male 129/Sv//Ev mice (38 versus 23%, P = 0.003). In
contrast, lack of the IFN-R in female mice did not affect mortality;
there were no differences in mortality in female 129/Sv//Ev, GKO, or RGKO mice.
Gender effects on HSV-1 reactivation.
To determine if gender
influences HSV-1 reactivation in vivo, the model of hyperthermic stress
was used (30) with modification. Briefly, mice were
subjected to three consecutive 10-min hyperthermia treatments (43°C)
separated by 3-h intervals, a modification shown to enhance the
efficiency of reactivation (R. L. Thompson, personal communication). The mice were thoroughly dried and kept warm under a
heat lamp after each treatment to avoid hypothermia. After 24 h,
the mice were euthanized, and then the trigeminal ganglia were removed,
homogenized, and assayed for infectious HSV-1 (6). Spontaneous reactivation or viral persistence was assessed in latently
infected mice not treated with hyperthermia by assaying ganglionic
homogenates for infectious HSV. The reactivation data obtained in
several experiments were pooled and analyzed statistically by using
Pearson's chi-square test with Yates' continuity correction.
We showed previously that persistent ganglionic infection or
spontaneous reactivation of HSV-1 did not occur in 129/Sv//Ev or GKO
mice (4). For the present experiments, latently infected male and female GKO, RGKO, and 129/Sv//Ev control mice were subjected to hyperthermic stress at 30 to 60 days postinfection, and reactivated HSV-1 was detected by assay of infectious virus in ganglionic homogenates. As shown in Table 2, there
was no difference in male and female129/Sv//Ev mice: reactivation
frequencies were 11 and 12%, respectively. However, the observed
frequency of reactivation in GKO mice was significantly greater in
males: 51% compared to 12% for females (P = 0.0005).
Similarly for RGKO mice, reactivation frequencies were higher in males
than females (33 versus 21%), but the difference did not reach
statistical significance (P = 0.17). As previously
reported (4), reactivation frequency was higher in the GKO
mice than in the 129/Sv//Ev controls. However, Table 2 shows that this
difference was derived only from male mice; there was no statistically
significant difference in reactivation in female RGKO or GKO mice
compared to female 129/Sv//Ev mice (Table 2). This result, together
with our mortality data (Table 1), suggests that, under certain
circumstances, IFN- has a more important role in males than in
females.
We suggested previously that rather than influencing the reactivation
process itself (i.e., molecular latency), IFN- controlled reactivating virus, making it less likely that infectious HSV would be found in ganglionic homogenates or HSV antigens detected by
immunohistochemistry (i.e., the IFN effect is on biological latency)
(4). There are at least three possible explanations for
the gender difference in reactivation shown in Table 2. First, the
burden of HSV DNA at the latent stage, a suggested predictor of HSV
reactivation (23, 25, 29), may be greater in male mice.
Although we cannot exclude this possibility, it seems unlikely, since
we found equivalent ganglionic HSV titers at the acute stage of
infection in male and female mice (Fig. 1). Second, the effects of
hyperthermic stress may be greater in males, so that reactivation from
molecular latency occurs more frequently in males than in females.
Failure to detect a gender difference in 129/Sv//Ev mice can explained
by the dampening effect of IFN- maintaining biological latency in
most of the 129/Sv//Ev males. However, in the absence of IFN-
signaling, as in RGKO and GKO mice, the gender difference is readily
apparent. The third possibility assumes that the levels of
hyperthermia-induced reactivation from molecular latency are equivalent
in male and female mice of all three strains, but female mice, with or
without IFN- signaling, have a more efficient immunological repertoire to maintain biological latency. We have no data to differentiate between the second and third possibilities, but we favor
immunological differences accounting for at least some of our results.
Our observation of greater HSV-1 reactivation frequency in male mice
(Table 2) is consistent with a report of a higher frequency of HSV-2
recurrence in men than in women (27). More detailed gender
comparisons of HSV infection in humans would be of interest to detect
differences similar to those we report here in mice. A recent report
that a gD2 subunit vaccine was effective in preventing genital herpes
disease in females, but not in males, is consistent with the notion
that immune responses to HSV-1 are affected by gender (S. Spruance,
Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., addendum
abstr. L6, p. 22, 2000).
Periocular eye disease is worse in testosterone-treated mice.
To determine a role for sex hormones in HSV-1 gender differences, we
evaluated periocular skin and eye disease in male mice and female mice
that received implants of either timed-release dihydrotestosterone
(DHT) pellets or placebo pellets. In this trial, RGKO mice were used,
since a consistent gender difference in mortality and reactivation had
been demonstrated in RGKO mice (Tables 1 and 2), and use of IFN-
null mutant mice eliminates any potential effect of estrogen on the
IFN- promoter. We evaluated 56 mice for eye disease: 18 males, 20 DHT-treated females, and 18 placebo-treated females. As shown in Fig.
2, extensive periocular hair loss
associated with skin breakdown and bleeding and lid edema producing eye
closure were observed in male and DHT-treated female mice 2 weeks after
HSV-1 inoculation, while the severity of these signs was noticeably
reduced in the placebo-treated female mice. An observer skilled in
assessing HSV eye disease, but unaware of the identity of the mouse
groups, graded periocular hair loss and skin changes at 17 days after
HSV-1 inoculation as follows: 0, no abnormality; 1, eyelid hair loss;
2, periocular hair loss extending <3 mm from the eyelid; 3, more
extensive hair loss, but not involving the entire right side of the
head; 4, hair loss on the entire right side of the head; and 5, skin
breakdown with bleeding on the right side of the head. These clinical
scores reflect the extent of HSV-1-induced lesions at the acute stage of infection. As shown in Fig. 3, there
was considerable overlap in the eye disease scores in the three
inoculation groups. However, none of the females had scores of 5, whereas three males and two DHT-treated females were scored at this
highest level of disease severity.
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FIG. 2.
HSV eyelid and periocular skin disease. A photograph of
representative mice from each of the male, placebo-treated female, and
DHT-treated female groups of mice shows severity of eyelid disease and
periocular skin disease 2 weeks after corneal inoculation of HSV-1.
Hair loss and skin lesions are prominent in the right eye of male and
DHT-treated female mice, but not placebo-treated female mice (the
affected area is indicated).
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FIG. 3.
Clinical eye disease scores. Scores for periocular skin
and eye disease in individual RGKO male, placebo-treated female, and
DHT-treated female mice 2 weeks after HSV-1 inoculation of the right
eye are presented. Horizontal bars indicate the mean scores.
|
|
To evaluate the hypothesis of more severe disease in male mice, the
individual scores in the male group and the two groups of female mice
were analyzed as ordered categories, by ordinal logistic regression to
test for linear-by-linear association. The experimental groups were
regarded as ordered categories with regard to testosterone levels, with
DHT-treated females considered intermediate between males and
placebo-treated females based on DHT treatment. Computing was done with
SAS release 6.12 for Windows NT version 4. Where multiple versions of a
test were computed (e.g., likelihood ratio and score tests), the more
conservative result is given. The ordinal logistic regression of
clinical scores revealed a positive association between skin disease
severity and the ordering of the groups with regard to testosterone
levels (P = 0.026), but corneal disease scores (not
shown) were not significantly different. No departures from the
logit-scale additivity assumed in the ordinal regression were detected
(P > 0.6).
IFN--dependent mechanisms have been reported to play a crucial role
in the control of HSV periocular skin lesions (17, 31,
34). Consistent with these reports, we found more severe periocular skin and eyelid disease in male RGKO mice than in male 129/Sv//Ev mice. However, similar to our results on mortality (Table 1)
and reactivation (Table 2), no clinical eye disease difference was
noted in a comparison of female RGKO and female 129/Sv//Ev mice (not
shown). These observations further underscore HSV gender differences
and also show that some mechanism other than IFN- accounts for the
milder eye disease in females.
Using a corneal disease rating scale without slit lamp biomicroscopy,
we found more severe corneal disease in males, but unlike periocular
skin disease, the gender difference for corneal disease did not reach
significance. Published studies have shown that the development of
corneal eye disease is strongly correlated with an inflammatory
response characterized by CD4+ Th1
cytokine-producing T cells (14, 17, 26), whereas disease remission is accompanied by a shift to a Th2 profile (2,
9). To determine whether there are differences in specific
cytokine production in our system, we have done quantitative reverse
transcription-PCR assays of spleen cell cultures restimulated with
HSV-1 antigen 72 h prior to the assay. Preliminary results with
pooled RNA samples from mice in each group indicated that males and
DHT-treated females had a Th1-like profile, producing IFN- and
interleukin 12 (IL-12) mRNA transcripts. In contrast, placebo-treated
females had a Th2-like profile, producing IL-4 and IL-10 and much lower
levels of IFN- and IL-12 mRNA transcripts (not shown). Whether DHT
reproducibly shifts cytokine profiles from Th2 to Th1 patterns in
HSV-1-infected female mice awaits more definitive demonstration in
individual as opposed to pooled mice.
The influence of sex hormones on the immune response has only recently
been appreciated as a potentially important factor in the development
of certain diseases (10, 37). In humans, myocarditis
associated with coxsackievirus infection occurs predominantly in
adolescent and adult males. Studies in the murine coxsackievirus model
(CVB3) revealed that estrogen mediates resistance to CVB3-induced myocarditis, whereas elevated testosterone and progesterone levels in
males and pregnant females confer susceptibility (24).
Importantly, further studies revealed that testosterone treatment
favored development of myocarditis by promoting induction of
CD4+ Th1 cells secreting IFN-, whereas
estrogen induced protective CD4+ Th2 cells
secreting IL-4 (21). In another example of sex hormones influencing the immune response and disease outcome, testosterone treatment of female mice was shown to protect against the development of EAE through the induction of a biased Th2 response involving IL-10
production (10). The regulation of cytokine synthesis by
steroid hormones in a variety of cell types suggests a possible role of
sex hormones in regulating the balance between Th1- and Th2-type
responses (7, 12). In principle, sex hormones could modulate the immune response and thereby affect the outcome of infection and disease. From limited studies, it is apparent that treatment with sex hormones in different disease or infection models
can have vastly different outcomes, reflecting the complex interactions
between sex hormones, the hypothalamic-pituitary-adrenal axis, and the
immune system under the influence of the target tissues, the local
physiological milieu, the genetic background, and the age of the
animals (36).
In summary, we have shown that there are significant gender differences
in mortality, virus reactivation, and clinical disease after HSV-1
inoculation of mice. There are probably multiple, yet to be described
mechanisms for these differences. However, a novel finding of our study
is that gender markedly affected the response of the GKO and RGKO mice
to HSV-1 inoculation: in a comparison of null mutant to control mice,
mortality and reactivation differences were seen only in males. This
finding implies that some normal functions of IFN- are gender
specific, in that IFN- plays a more important role in HSV-1
infection in male mice than in female mice. Although the IFN-
promoter has been shown to be regulated by estrogen in vitro
(13), to the best of our knowledge, this is the first
report documenting in vivo gender-specific effects of IFN-.
This work was supported by Public Health Service grant MH55784 from the
National Institute of Mental Health.
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Abstract
Text
Present address: Harbor UCLA REI, Division of Medical Genetics,
Torrance, CA 90502.
