Type III interferons suppress influenza A virus infection independently of STAT activation by triggering cell death

Abstract

Type III interferons (IFN-{lambda}1-{lambda}4) are known to limit influenza virus infections in vivo and are non-redundant to type I interferons (IFN- and IFN-{beta}). Here, we demonstrate that IFN-{lambda} acts through mechanisms that are beyond its ability to induce JAK/STAT signaling and promotes fast cell death in epithelial cells stimulated with poly(I:C). Studying influenza A virus (IAV) and respiratory syncytial virus (RSV) infections in vitro we notice that type I interferons, when provided prior to infection, induce higher STAT1/2 activation and a stronger accumulation of proteins coded by interferon-stimulated genes, and correspondingly suppress both IAV and RSV spread more effectively than type III interferons. The knockout of the IFN-{lambda} receptor (subunit IFNLR1), compared to the knockout of the IFN-{beta} receptor (subunit IFNAR1), only slightly influences levels of STAT1/2 phosphorylation during infection with any of the viruses; However, IFNLR1 knockout results in a greater proportion of IAV-infected cells and higher viral RNA and protein levels. We showed that the ratio of dying to infected cells is lower in IFNLR1-deficient cells compared to wild-type cells, suggesting that IFN-{lambda} promotes the rapid death of IAV-infected cells and thereby limits viral spread. This effect was not observed in RSV-infected cultures, possibly due to the RSVs ability to suppress host cell death through its nonstructural proteins. Overall, our results reveal a distinct role for IFN-{lambda} in restricting viral infections by triggering rapid death of infected epithelial cells, in contrast to type I interferons, which are the main inducers of JAK/STAT-mediated expression of ISGs, that may be used by IFN-{lambda} to trigger cell death.