Elevated 17β-Estradiol Protects Females from Influenza A Virus Pathogenesis by Suppressing Inflammatory Responses

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Abstract
Studies of the 1918 H1N1 influenza pandemic, the H5N1 avian influenza outbreak, and the 2009 H1N1 pandemic illustrate that sex and pregnancy contribute to severe outcome from infection, suggesting a role for sex steroids. To test the hypothesis that the sexes respond differently to influenza, the pathogenesis of influenza A virus infection was investigated in adult male and female C57BL/6 mice. Influenza infection reduced reproductive function in females and resulted in greater body mass loss, hypothermia, and mortality in females than males. Whereas lung virus titers were similar between the sexes, females had higher induction of proinflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-6, and CCL2, in their lungs than males. Removal of the gonads in both sexes eliminated the sex difference in influenza pathogenesis. Manipulation of testosterone or dihydrotestosterone concentrations in males did not significantly impact virus pathogenesis. Conversely, females administered high doses of estradiol had a ≥10-fold lower induction of TNF-α and CCL2 in the lungs and increased rates of survival as compared with females that had either low or no estradiol. The protective effects of estradiol on proinflammatory cytokines and chemokines, morbidity, and mortality were primarily mediated by signaling through estrogen receptor α (ERα). In summary, females suffer a worse outcome from influenza A virus infection than males, which can be reversed by administration of high doses of estradiol to females and reflects differences in the induction of proinflammatory responses and not in virus load. Sex and pregnancy affect the outcome of infection with seasonal, avian, and pandemic influenza viruses among young adults. Males and females are biologically different, yet the implications of these differences on influenza A virus pathogenesis are not well characterized. Generally, females mount more robust immune responses to viral challenge than males, which can result in more efficient virus clearance at the cost of developing immune-mediated pathology. In this study, we tested the hypothesis that sex and sex steroid hormones differentially impact the outcome of influenza A virus infection in mice. Our data illustrate that influenza A virus dysregulates reproductive function as well as cytokine and chemokine production in females, rendering them significantly more susceptible to weight loss, hypothermia, and death than males. Administration of a high dose of estradiol or an estrogen receptor α agonist to females suppresses the excessive induction of cytokines and chemokines and increases survival following infection. The protective effects of estradiol on influenza pathogenesis reflect changes in the induction of proinflammatory responses and not in virus load. Uncovering the mechanisms mediating how sex and sex steroid hormones affect influenza pathogenesis may result in preventative measures and treatments that are optimized for both sexes.