The metabolic role of gut dysbiosis in altered T cell responses to influenza virus infection

Abstract

Abstract Commensal gut microbiota modulates protective immune responses to viral infections at extra-intestinal sites, including the lungs. Gut dysbiosis induced by broad-spectrum antibiotic treatment appears to alter adaptive immunity to influenza infection (IAV/PR8). However, the mechanism by which microbial metabolism influences immune responses across the gut-lung axis remains unclear. Here, we used flow cytometric analysis to investigate T cell responses to IAV in specific pathogen free (SPF), Altered Schaedler flora (ASF) and germ-free mice models. We show that, compared to SPF mice, ASF and germ-free mice have significantly reduced levels of regulatory T cells (Tregs) and virus specific cytotoxic CD4 and CD8 T cells at 10 days post infection. Further analysis of microbial mediators in the peripheral blood of these mice revealed significantly increased levels of L-arginine in the serum of ASF and germ-free mice compared to SPF mice. We noted that, germ-free and ASF mice lack bacteria that metabolize dietary amino acids, including L-arginine, regulating its increased availability in the peripheral blood of these mice. To investigate the role of L-arginine as a microbial mediator of reduced T cell responses to IAV, we supplemented L-arginine or administered neomycin (to induce selective disruption of arginine metabolizing bacteria) to separate cohorts of SPF mice. We observed altered cytotoxic and effector T cell responses at 10 days post infection in the experimental groups, however, Tregs were not significantly affected. Our data suggests that selective dysbiosis may increase L-arginine levels in the serum of SPF mice which may directly affect virus specific effector T cell responses in the lung mucosa.