Metabolic syndrome enhances viral disease severity and reduces vaccine efficacy in mice

Abstract

Abstract Metabolic syndrome (MetS) is a cluster of conditions linked by chronic inflammation that increase the risk for comorbidities. Currently, 1/3 of United States adults have MetS. Globally, obesity rates have tripled since 1975, which is notable since it is a criterium used to diagnose MetS. MetS patients show higher mortality post-SARS-CoV-2 infection and poor vaccination outcomes following influenza virus vaccination when compared to metabolically healthy humans. However, the mechanisms driving MetS-induced immune dysfunction are unknown. Based on previously published work, we hypothesize that MetS-associated chronic inflammation alters programming of adaptive immune cells critical for viral control, thus enhancing disease severity and reducing vaccine efficacy. To challenge this, we use West Nile virus and SARS-CoV-2 in MetS murine models. By infecting or vaccinating chow fed wild type (WT) and high fat diet induced MetS mice, we compared immune responses over time. Our results indicate that MetS mice have higher mortality post infection, heightened viral titers, severe organ pathology, dysfunctional T and B cell responses and reduced neutralizing antibody efficacy when compared to WT mice. Further, MetS alters antibody and T cell responses post-vaccination, rendering vaccination insufficient for protecting against severe viral disease. Our results imply that MetS enhances viral disease severity and reduces vaccine efficacy. Ongoing studies in our lab are focused on determining the mechanism by which MetS alters adaptive immune cell function, with our data implicating chronic inflammation as an inducer of immune cell epigenetic changes that alter their differentiation landscapes and consequently effector functions. Supported by grants from NIH (R01 12781495) and DoD (USAMRDCPR192269).