IFITMs inhibit infection of diverse enveloped viruses, including the Influenza A virus, West Nile, Ebola and others. Using single virus imaging, we have shown that IFITM3 concentrates at the sites of Influenza virus entry and allows lipid mixing but abrogates the release of viral content into the cytoplasm (Figure 4, Movies 3 and 4). We also found that arenaviruses, which are resistant to IFITM restriction, can traffic and fuse with endosomal compartments devoid of IFITM3. We have shown that IFITM3 imposes negative curvature and increases rigidity of the cytoplasmic leaflet of a target membrane, thereby disfavoring the formation of fusion pores and trapping virions at a hemifusion intermediate. We are currently employing correlative light-electron microscopy (CLEM, Figure 5) approaches to study IFITM-mediated virus restriction and its antagonism by cyclosporin A.
