Influenza A Virus Induces LDHA Expression and Lactate Formation to Inhibit Type I IFN and Promote Replication in Primary Human Airway Epithelium

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 Lactate promote IAV but not SARS-CoV-2 replication by inhibiting MAVS-dependent induction of type I IFN in primary human airway epithelium. Funding Statement: This research work was supported by the Graduate School of Health Aarhus University, Fhv. Dir. Leo Nielsen & Hustru Karen Margrethe Nielsens Legat for Laegevidenskabelig Grundforskning, Ester M. & Konrad Kristian Sigurdssons Dyrevaernsfond, Beckett-fonden, Kong Christian IX & Dronning Louises Jubilaeumslegat, Christian Larsen & Dommer Ellen Larsens Legat, Direktor Emil C. Hertz & hustru Inger Hertz’ fond og A.P. Moller Fonden. SC and AW were supported by the Francis Crick Institute which receives its core funding from Cancer Research UK (FC001206), the UK Medical Council (FC001206), and the Wellcome Trust (FC001206). Declaration of Interests: The authors declare no competing interests.