Mechanisms of sex disparities in influenza pathogenesis

Abstract

Epidemiological evidence from influenza outbreaks and pandemics reveals that morbidity and mortality are often higher for women than men. Sex differences in the outcome of influenza are age-dependent, often being most pronounced among adults of reproductive ages (18-49 years of age) and sometimes reflecting the unique state of pregnancy in females, which is a risk factor for severe disease. Small animal models of influenza virus infection illustrate that inflammatory immune responses also differ between the sexes and impact the outcome of infection, with females generating higher proinflammatory cytokine and chemokine responses and experiencing greater morbidity and mortality than males. Males and females also respond differently to influenza vaccines, with women initiating higher humoral immune responses but experiencing more adverse reactions to seasonal influenza vaccines than men. Small animal models further show that elevated immunity following vaccination in females leads to greater cross-protection against novel influenza viruses in females compared with males. Sex steroid hormones, including estradiol and testosterone, as well as genetic differences between the sexes may play roles in modulating sex differences in immune responses to influenza virus infection and vaccination. Future studies must elucidate the pathways and cellular responses that differ between the sexes and determine how best to use this knowledge to inform public health policy-makers about prophylaxis and therapeutic treatments of influenza virus infections to ensure adequate protection in both males and females.

Figure 1.. Hypothesized mechanisms mediating sex differences in the outcome of influenza virus infection.

In female mice, infection results in persistently low levels of E2, causing enhanced activity of NF-κB and proinflammatory cytokine and chemokine responses in the lungs. Greater induction of chemokines, in particular, might result in an excessive influx of immune cells and development of immunopathology in females (A). In male mice, although influenza virus infection suppresses T concentrations, this does not cause excessive, proinflammatory responses or development of immunopathology (B). Solid arrows indicate relationships demonstrated by our laboratory and others [15, 35]; broken arrows indicate hypothesized relationships that have not yet been demonstrated. IAV, Influenza A virus.

Figure 2.. The balance between proinflammatory and anti-inflammatory mechanisms differs between the sexes and results in a differential outcome of influenza virus infection.

During influenza virus infection, females show a greater induction of proinflammatory responses, including CCL2, TNF-α, IFN-γ, and IL-6, than males. Heightened proinflammatory responses may involve activation of inflammatory cells, proteins, and pathways that increase the risk of immunopathology in females compared with males. Conversely, in males, excessive induction of anti-inflammatory or regulatory responses may increase their risk of persistent viral infection. T_reg, Regulatory T cell.