Microbiota-derived acetate is associated with functionally optimal virus-specific CD8 ⁺ T cell responses to influenza virus infection via GPR43-dependent metabolic reprogramming

The microbiota-associated factors that affect host susceptibility and adaptive immunity to influenza A virus (IAV) infection have not been fully elucidated. By comparing the microbiota composition between survivors and mice that succumbed to IAV strain PR8 infection, we identified that the commensal bacterium <i>Blautia coccoides</i> protects antibiotics (Abx)-treated or germ-free (GF) mice from PR8 infection by inducing functionally optimal virus-specific CD8⁺ T cell responses. Administration of exogenous acetate reproduced the protective effect of <i>B. coccoides</i> monocolonization in Abx and GF mice, enhancing oxidative phosphorylation and glycolysis as well as secretion of IFN-γ and granzyme B in virus-specific CD8⁺ T cells, dependent on GPR43 signaling and acetyl-CoA synthetase 2. Thus, we have demonstrated that microbiota-derived acetate possesses an antiviral effect that induces an optimal virus-specific CD8⁺ T cell response to IAV PR8 infection via GPR43-dependent metabolic reprogramming.