Investigating the role of IFITM proteins in the viral entry mechanism of early and Omicron variants

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a global health challenge due to the emergence of viral variants with altered entry mechanisms, making host restriction factors such as interferon-induced transmembrane proteins (IFITMs) critical determinants of infectivity. This study investigated the role of IFITM1, IFITM2, and IFITM3 in mediating the entry of early SARS-CoV-2 variants and Omicron subvariants using pseudotyped virus systems in human lung epithelial cells, with viral entry quantified by luciferase-based assays following IFITM overexpression. The results demonstrate that IFITM1 significantly restricts viral entry for several early variants, while IFITM2 exhibits consistent inhibitory effects across all variants examined. In contrast, IFITM3 overexpression does not significantly alter viral entry efficiency for any variant tested, indicating that IFITM3 does not play a major restrictive role in this experimental system. Collectively, these findings highlight distinct functional differences among IFITM family members and emphasise the importance of variant-specific entry pathways in shaping susceptibility to host restriction factors.