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.
Highlights
Males and females differ in their responses to infection with many viral pathogens, including human immunodeficiency virus (HIV), herpes simplex viruses, and hantaviruses [1]
Females mount more robust immune responses to viral challenge than males, which can result in more efficient virus clearance at the cost of developing immunemediated pathology
We tested the hypothesis that sex and sex steroid hormones differentially impact the outcome of influenza A virus infection in mice
Summary
Males and females differ in their responses to infection with many viral pathogens, including human immunodeficiency virus (HIV), herpes simplex viruses, and hantaviruses [1]. Because females tend to mount higher innate [4,5], cell-mediated [5,6,7], and humoral [8] immune responses than males, viral loads are often reduced among females [1]. Estradiol (E2) can have divergent effects, with low doses enhancing proinflammatory cytokine production (e.g., IL-1, IL-6, and TNF-a) and T helper cell type 1 (Th1) responses and high or sustained concentrations reducing production of proinflammatory cytokines and augmenting Th2 responses and humoral immunity [15]. The anti-inflammatory effects of high E2 are mediated by signaling through estrogen receptors (ERs), which inhibits activation of NF-kB-mediated inflammatory responses [20]
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