Influenza A induces lactate formation to inhibit type I IFN in primary human airway epithelium

Thyrsted, Jacob Storgaard Jacob Blay-Cadanet Julia Heinz Alexander Thielke Anne Laugaard Crotta Stefania de Paoli Frank Olagnier David Wack Andreas Hiller Karsten Hansen Anne Louise Holm Christian Kanstrup

Summary: Pathogenic viruses induce metabolic changes in host cells to secure availability of biomolecules and energy to propagate. Influenza A virus and SARS-CoV-2 both infect the human airway epithelium and are important human pathogens. The metabolic changes induced by these viruses in a physiologically relevant human model, and how this affects innate immune responses to limit viral propagation is not well known. Using an ex vivo model of pseudostratified primary human airway epithelium, we here demonstrate that infection with both IAV and SARS-CoV-2 resulted in distinct metabolic changes including increases in lactate Dehydrogenase A (LDHA) expression and LDHA-mediated lactate formation. Interestingly, LDHA regulated both basal and induced MAVS-dependent type I interferon (IFN) responses to promote IAV, but not SARS-CoV-2, replication. Our data demonstrate that LDHA and promote IAV but not SARS-CoV-2 replication by inhibiting MAVS-dependent induction of type I IFN in primary human airway epithelium.