Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis

Wild-type (WT) male and female C57BL/6 mice were assigned to remain intact or be gonadectomized (Gdx) and all FCG mice on a C57BL/6 background were Gdx. Mice were infected with either CVB3 or mouse-adapted IAV, A/Puerto Rico/8/1934 (PR8), and monitored for changes in immunity, virus titers, morbidity, or mortality.In CVB3 infection, mortality was increased in WT males compared to females and males developed more severe cardiac inflammation. Gonadectomy suppressed male, but increased female, susceptibility to CVB3. Infection with IAV resulted in greater morbidity and mortality in WT females compared with males and this sex difference was significantly reduced by gonadectomy of male and female mice. In Gdx FCG mice infected with CVB3, XY mice were less susceptible than XX mice. Protection correlated with increased CD4+ forkhead box P3 (FoxP3)+ T regulatory (Treg) cell activation in these animals. Neither CD4+ interferon (IFN)γ (T helper 1 (Th1)) nor CD4+ interleukin (IL)-4+ (Th2) responses differed among the FCG mice during CVB3 infection. Infection of Gdx FCG mice revealed no effect of sex chromosome complement on morbidity or mortality following IAV infection.These studies indicate that sex chromosome complement can influence pathogenicity of some, but not all, viruses.Males and females differ in their susceptibility to a variety of viral pathogens [1]. The mechanisms for this sexual dimorphism are complex and can involve hormonal, behavioral and genetic factors. Females typically generate enhanced immune responses compared to males [2-4], which can accelerate virus clearance and reduce virus load, but can be detrimental by causing immunopathology or the development of autoimmune disease. Immunity to viruses varies with changes in hormone concentrations caused by natural fluctuations over the menstrual or estrous cycle, contraception use, and pregnancy [5]. Estradiol influences multiple aspects of both innate and adaptive immunity including: enhancing dendritic cell