Hormonal Changes During Physiological Development Can Alter Immune Response To Viruses And Infections

Why men and women respond differently to infections caused by viruses or other parasites remains a mystery. How the immune system adopts certain strategies towards particular illnesses has not been determined. Examining gender characteristics, hormones and genes, and how they interact with immunology could provide answers to these questions. This was the goal of a team of Johns Hopkins researchers as they set out to determine how differences in sex are expressed in rats' response to hantaviruses (sex differences in hantaviruses represent an ecologically and clinically relevant model for studies of sex-based differences in infection).

Researchers Sabra L. Klein, Ph.D., A.L. Scott, and G.E. Glass, Ph.D., all from the Department of Molecular Microbiology and Immunology, The Johns Hopkins University Bloomberg School of Public Health, Baltimore, Md., have conducted a study on "Sex Differences in Hantavirus Infection: Interactions Among Hormones, Genes, and Immunity." Their findings are to be presented at the conference, Genomes and Hormones: An Integrative Approach to Gender Differences in Physiology, being sponsored by the American Physiological Society (APS) October 17-20, 2001, at the Westin Convention Center, Pittsburgh, Pa.

Methodology and Results

These researchers first set out to determine if manipulating sex steroids in adult rodents would impact the response to inoculation with the Seoul virus (a Hantavirus that naturally occurs in Norway rats). The researchers found that in the male rats, the production of antibodies increased, enhanced Th1 responses (inflammatory responses) against infection occurred, and shed or released the virus into the environment for a longer time period than comparable females in the study. Accordingly, hormone manipulation in female and male adult rodents had no effect on their normal response to virus infection.

In all animals (including humans), sex steroid hormones affect gender-specific development at two distinct times. During perinatal (i.e., during prenatal and early postnatal) development, sex steroids cause permanent, hard-wired differences in the organization of central and peripheral physiology (i.e., organizational effects). After puberty, exposure to sex steroids serves to transiently activate pre?existing hormonal circuits (i.e., activational effects). In mammals, masculine development is induced by early exposure to testosterone, whereas feminine development occurs in the absence of testosterone. Because manipulation of hormones in adult animals had no effect on responses to viral infection, these researchers hypothesized that hormones may hard-wire gender-specific immune responses earlier during development.

Therefore, the next step in the study was to determine if neonatal manipulation of sex hormones organized adult responses to the hantavirus administered to rats. After two to four days of age, male rats were castrated and females were injected with testosterone. All animals were inoculated with the Seoul virus as adults; antibody responses and viral prevalence were assessed in both sexes.

Castrated males displayed female-type responses, i.e. lower concentrations of anti-virus responses with less virus shed than in the control male population. On the other hand, injecting testosterone into female neonatal mice had no impact on that group's response to infection.

Conclusions

Altering the immune response to infection occurs at a neonatal stage, as evidenced by the lowering levels of testosterone in male mice. However, manipulating testosterone levels in female mice had no impact on the immune system. These results suggest that the preponderance of gender-related immunological diseases must be related to mechanisms other than sex steroids alone, possibly genetic differences between the sexes.

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.