Sex differences in innate anti-viral immune responses to respiratory viruses

Males have excess morbidity and mortality from respiratory viral infections and especially so in COVID-19. The mechanisms explaining this excess in disease burden in males are unknown. Innate immune responses are likely critical in protection against a novel virus like SARS-CoV-2. We hypothesised that innate immune responses may be deficient in males relative to females. To test this we stimulated peripheral blood mononuclear cells (PBMCs) from participants in a population-based birth cohort with three respiratory viruses (rhinoviruses-RV-A16 and RV-A1, and respiratory syncytial virus-RSV) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2). We measured interferon (IFN) and IFN-induced chemokine responses and investigated sex differences in virus-induced responses. IFN-α, IFN-β and IFN-γ responses to RV-A16 were deficient in males compared to females, fold-inductions being 1.92-fold (P<0.001), 2.04-fold (PP=0.003) lower in males than females, respectively. Similar significant deficiencies in innate immune responses were observed in males for eleven other cytokine-stimulus pairs. Responses in males were greater than those in females in only one of 35 cytokine-stimulus pairs investigated. Review of healthcare records revealed that 12.1% of males but only 6.6% of females were admitted to hospital with respiratory infections in the first year of life (P=0.017). Impaired innate anti-viral immunity in males likely results in high morbidity and mortality from respiratory viruses including COVID-19. Males may preferentially benefit from therapies that boost innate anti-viral immune responses.Significance StatementClinical outcomes including, mortality, Intensive care unit admissions and hospital admissions, during COVID-19 disease are consistently and substantially worse in males than in females. The mechanisms underlying this increased susceptibility to severe disease in males are not understood. We hypothesised that the differential outcomes between sexes could be a consequence of deficient innate interferon responses in males, and more robust innate interferon responses in females. We have investigated such responses in a large population-based cohort and found that indeed males have deficient innate interferon responses to viral stimuli, including stimuli that mimic SARS-CoV-2 infection, relative to females. Our findings have very important treatment implications as interferons are available for clinical use with immediate effect.