CD26 acts as a host restriction factor to inhibit Influenza A virus (H1N1) infection

The frequent mutations and emerging drug resistance of Influenza A virus (IAV) pose a persistent global health challenge. The identification of host restriction factors that can inhibit viral infection is crucial for the development of novel antiviral therapies. CD26 acts as a host restriction factor in inhibiting H1N1 infection and the underlying mechanisms remain unclear. Our findings collectively demonstrate that CD26 inhibits H1N1 infection. In vitro, soluble CD26 (2.5 μg/ml) reduces H1N1 titers, specifically suppresses IL-6 upregulation in H1N1-infected A549 cells via NF-κB/IRF3/STAT1 signaling, and dose-dependently inhibits viral hemagglutinin (HA) expression. Surface Plasmon Resonance (SPR) assays confirm direct binding between sCD26 and H1N1 HA with a dissociation constant of 616 nM, while confocal microscopy demonstrates their colocalization, supporting the interaction. As compared with H1N1-infected Wild-Type mice, H1N1-infected CD26 knockout mice showed uncontrolled viral spread, more severe lung pathology, altered lung immune cell proportions, and elevated CXCL2/IL-1β/IL-6 levels in bronchoalveolar lavage fluid (BALF). Overall, this study identifies CD26 as a host restriction factor against H1N1, thereby providing a potential therapeutic avenue for managing influenza-induced lung complications.