Type III interferons disrupt the lung epithelial barrier upon viral recognition

Lower respiratory tract viral infections are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. Here, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report IFN-λ is present in the lower, but not upper, airways of COVID-19 patients. In mice, we demonstrate IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in the clinical practice against endemic viruses, such as influenza virus, as well as the emerging SARS-CoV-2 viral infection.