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

Introduction

Influenza is an acute respiratory immunopathology resulting from the intrinsic pathogenicity of influenza A (IAV) and B (IBV) viruses, added to an inflammatory host response, which in excess, is deleterious. Influenza is a major public health issue, causing 500,000 deaths per year and a considerable socioeconomic burden. Frequent vaccine escape and emerging antiviral resistance spur innovative research on host-directed therapy against influenza. In that regard, some host metabolites have emerged as potent immuno-regulatory molecules.

Methods

We recently characterized mitochondria-derived succinate as a major antiviral metabolite (EMBO J., 2022). Here, we extended those findings by screening the effect of other host metabolites on influenza virus infection, using human bronchial epithelial cells. Among these metabolites, we focused on one mitochondria-derived metabolite (coined here “C2”) and evaluated its anti-inflammatory and antiviral activity using complementary approaches, such as immunological and qRT-PCR assays, reverse genetics, western-blotting, flow cytometry and confocal microscopy techniques.

Results

We found that 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 TNFα. 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: 70% and 0%, respectively).

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.