Female obese mice have a higher mortality rate and altered immune responses following flavivirus infection in comparison to wild type mice Elizabeth Geerling1, Mariah Hassert1, E Taylor Stone1, Tara L. Steffen1 and Amelia K. Pinto1 1Saint Louis University, St. Louis, MO 63104 Department of Molecular Microbiology and Immunology A rise in adiposity in the United States has resulted in more than 70% of adults being overweight or obese (National Center for Health Statistics). Globally, areas that have seen a dramatic rise in obesity have also seen a significant increase in emerging arboviral pathogens. Regions of South and Central America have particularly suffered from this “double disease burden” (World Health Organization). Studies done using influenza, hepatitis C, West Nile and dengue viruses have shown that excessive adiposity increases host susceptibility to viral infection and alters immune responses to vaccination. Similarly, obese individuals have a greater risk for developing COVID-19 following SARS-CoV-2 infection, with longer average hospital stays and a higher mortality rate when compared to non-obese individuals. However, limited research has been done to identify mechanisms responsible for impaired immune function. Based on published studies and our preliminary data, we hypothesized that obesity-associated chronic inflammation alters the immune system, enhancing susceptibility to viral diseases and hindering vaccine efficacy. To study how obesity-associated immune inflammation impacts virus disease severity, we are using West Nile virus and SARS-CoV-2 in murine models of obesity. By infecting regular chow-fed (wt) and high fat diet-induced obese (ob) mice, we compared virus-specific immune responses at different time points post infection. Results from these studies indicate that female ob mice have a higher mortality rate, dysfunctional virus-specific T cell responses and lowered efficacy of neutralizing antibodies. These results demonstrate that obesity can lead to enhanced disease severity following viral infection and may have long term consequences for the generation of protective immune responses to vaccination. We are currently conducting studies to determine if immune cells primed in the obese environment are protective, if chronic inflammation leads to epigenetic changes that alter T cell effector functions, the role of sex steroid hormones in immune response differences between male and female ob mice and differences in immunological responses and protection from lethal challenge between wt and ob mice following vaccination.