Sex-specific Immune Responses to Severe Influenza Virus Infection

Sex-specific Immune Responses to Severe Influenza Virus Infection ABSTRACT Men and women experience influenza virus infection differently, with women often experiencing a more severe infection. Lung immunopathology is a major contributing factor to influenza virus disease severity and has been linked to differential disease outcomes in men and women. The differences between male and female immune responses during infection are the immune response dynamics, i.e. the speed and magnitude of the reaction of key immune molecules and cells to the virus. These dynamics are regulated by the molecular and cellular interactions that comprise the lung immune system, and it has been shown that lung immune dynamics can be altered in women by altering levels of circulating sex steroids (estradiol) to affect lung inflammation and overall infection severity. Here, we propose an experimental and computational modeling study to quantify the differential immune kinetics that drive the distinct lung immunopathological outcomes observed between men and women. Human male and female infection outcomes have been recapitulated in mouse models. We will infect male and female mice with a moderate pandemic H1N1 virus and a deadly avian influenza virus, collect dynamic immunologic and hormone data, and train mathematical models to the data to quantify the immune kinetics regulating the differential dynamic lung immune responses observed between the sexes. The immunologic data will include major cytokines and immune cells with established significance to virus clearance and respiratory tissue inflammation. Successful completion of the research program will provide the first sex- specific mathematical models of influenza-induced immune responses, the first mathematical models of the avian influenza induced immune response, and the first mathematical models quantifying the impact of sex hormones on lung immune regulation in females. By quantifying which immune kinetics are different between males and females during moderately and severely pathogenic infections, we will generate novel hypotheses on the molecular/cellular origins of lung immunopathology during influenza infection and provide quantitative evidence on whether mechanisms promoting severe lung pathology are dependent on sex, virulence of the virus, or both factors. And quantifying the relationship between sex hormones and lung immune activity in females may provide insight into the mechanisms associated with the increased susceptibility experienced by pregnant women during severe influenza virus infection.