The ongoing COVID-19 pandemic has increased awareness about sex-specific differences in immunity and outcomes following respiratory virus infections. Strong evidence of a male bias in COVID-19 disease severity will be presented based on clinical data and preclinical animals models, which illustrate sex differential immune responses against SARS-CoV-2. Prior to the pandemic, data from other viral infections, including influenza viruses, showed profound sex differences in virus-specific immunity, including locally in the respiratory tract. We have used influenza A viruses to interrogate sex-specific immunity to infection and vaccination. Although males are more susceptible to most viral infections, females possess immunological features that contribute to greater vulnerability to immune-mediated pathology but also better protection following vaccination. Both sex chromosome complement and related X-linked genes (e.g., TLR7) as well as sex steroids, including estrogens and androgens, play important roles in mediating the development of sex differences in immunity to respiratory viral infections and vaccination.
1. Definition of biological sex and distinction from gender, with consideration of diverse respiratory viruses.
2. Characterization of sex differences in respiratory virus pathogenesis in humans and animal models, with emphasis on influenza A viruses and SARS-CoV-2.
3. Insights into the genetic and hormonal mechanisms that underlie sex differences in immunity to respiratory virus infection and vaccination.