Identification of a host antiviral and anti-inflammatory metabolite that protects against influenza virus-driven morbidity and mortality

Influenza is a major public health issue, but current therapies provide suboptimal effectiveness. Because influenza pathogenesis results from both direct cytopathic viral effects and excessive inflammatory responses, we investigated an innovative metabolite-based therapy that could target both critical mechanisms. Indeed, multiple metabolites have recently emerged as immuno-regulatory and/or antimicrobial molecules. We recently characterized mitochondria-derived succinate as a major antiviral metabolite. Here, we extended those findings by screening the effect of other host metabolites on influenza virus infection, using human bronchial epithelial cells. We found that one of them (coined here “C2”) has a major antiviral activity by preventing the expression of viral mRNA and protein, and the subsequent multiplication of both influenza A and B virus strains. Next, we observed that C2 alleviates the inflammatory cascades triggered by influenza virus and other inflammatory stimuli, including the inflammatory cytokine TNFa. We further showed in a mouse model of influenza pneumonia that C2 decreases the viral load, the leukocyte recruitment into the airspaces, the secretion of inflammatory mediators and the damage of lung tissues. As a result, mice treated at day 2 post-infection with C2 resist better than non-treated animals to a lethal dose of influenza virus (survival rate: 80% and 0%, respectively). In conclusion, we reveal that C2 is a host metabolite with anti-viral and anti-inflammatory properties that protect against influenza pneumonia. Our results open new avenues for the development of a C2-based treatment of influenza virus infection.