Opposing activities of IFITM proteins in SARS‐CoV‐2 infection

Abstract

Interferon‐induced transmembrane proteins (IFITMs) restrict infections by many viruses, but a subset of IFITMs enhance infections by specific coronaviruses through currently unknown mechanisms. We show that SARS‐CoV‐2 Spike‐pseudotyped virus and genuine SARS‐CoV‐2 infections are generally restricted by human and mouse IFITM1, IFITM2, and IFITM3, using gain‐ and loss‐of‐function approaches. Mechanistically, SARS‐CoV‐2 restriction occurred independently of IFITM3 S ‐palmitoylation, indicating a restrictive capacity distinct from reported inhibition of other viruses. In contrast, the IFITM3 amphipathic helix and its amphipathic properties were required for virus restriction. Mutation of residues within the IFITM3 endocytosis‐promoting YxxΦ motif converted human IFITM3 into an enhancer of SARS‐CoV‐2 infection, and cell‐to‐cell fusion assays confirmed the ability of endocytic mutants to enhance Spike‐mediated fusion with the plasma membrane. Overexpression of TMPRSS2, which increases plasma membrane fusion versus endosome fusion of SARS‐CoV‐2, attenuated IFITM3 restriction and converted amphipathic helix mutants into infection enhancers. In sum, we uncover new pro‐ and anti‐viral mechanisms of IFITM3, with clear distinctions drawn between enhancement of viral infection at the plasma membrane and amphipathicity‐based mechanisms used for endosomal SARS‐CoV‐2 restriction.

Coinfection with influenza A virus enhances SARS-CoV-2 infectivity

“…On the contrary, both our data with pseudo-SARS-CoV-2 (Fig. 5d, g ) and others’ data with either pseudo 23 or live SARS-CoV-2 24 , 25 proved that exogenous IFN could strongly inhibit SARS-CoV-2 infection at least in cell cultures (probably through antiviral actions of numerous ISGs including IFMITs 23 ). Thus, we should distinguish the roles of endogenous and exogenous IFN in the coinfection model.…”

Syncytia formation by SARS‐CoV‐2‐infected cells

“…Future experiments with IFITM mutants lacking sorting signals or motifs involved in palmitoylation and other post‐translational modifications will help understanding how these proteins impact SARS‐CoV‐2 fusion. Furthermore, recent reports have suggested that IFITMs may either enhance or restrict SARS‐CoV‐2 infection, depending on the experimental system and the cell type (preprint: Bozzo et al , 2020; preprint: Shi et al , 2020). Future investigations into the role endogenous IFITMs and TMPRSS2 conducted with primary cells treated or not with type‐I IFN will provide a more thorough translational understanding of viral‐induced syncytia formation.…”

Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer’s disease

“…The IFITM family of proteins have been previously recognized as important regulators of MERS-CoV-2 and SARS-CoV-2 virulence, either by physiological restriction of their entry, or as infection enhancers, following loss-of-function mutations. 12 IFITM3 was found to be upregulated in SARS-CoV-2 -infected cells 13 , 14 ; furthermore, specific polymorphisms, such as the rs12252-C have been identified as severity markers for COVID-19. 15 A current concept for SARS-CoV-2’s immunoevasion of IFITM3 sequestration involves cleavage by TMPRSS2.…”