IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro

Prelli Bozzo, Caterina; Nchioua, Rayhane; Volcic, Meta; Koepke, Lennart; Krüger, Jana; Schütz, Desiree; Heller, Sandra; Stürzel, Christina M.; Kmiec, Dorota; Conzelmann, Carina; Müller, Janis; Zech, Fabian; Braun, Elisabeth; Groß, Rüdiger; Wettstein, Lukas; Weil, Tatjana; Weiß, Johanna; Diofano, Federica; Rodríguez Alfonso, Armando A.; Wiese, Sebastian; Sauter, Daniel; Münch, Jan; Goffinet, Christine; Catanese, Alberto; Schön, Michael; Boeckers, Tobias M.; Stenger, Steffen; Sato, Kei; Just, Steffen; Kleger, Alexander; Sparrer, Konstantin M. J.; Kirchhoff, Frank

Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) can restrict viral pathogens, but pro- and anti-viral activities have been reported for coronaviruses. Here, we show that artificial overexpression of IFITMs blocks SARS-CoV-2 infection. However, endogenous IFITM expression supports efficient infection of SARS-CoV-2 in human lung cells. Our results indicate that the SARS-CoV-2 Spike protein interacts with IFITMs and hijacks them for efficient viral infection. IFITM proteins were expressed and further induced by interferons in human lung, gut, heart and brain cells. IFITM-derived peptides and targeting antibodies inhibit SARS-CoV-2 entry and replication in human lung cells, cardiomyocytes and gut organoids. Our results show that IFITM proteins are cofactors for efficient SARS-CoV-2 infection of human cell types representing in vivo targets for viral transmission, dissemination and pathogenesis and are potential targets for therapeutic approaches.