SARS-CoV-2 VOCs Dependent On IFITM2 For Replication


A new study by researchers from the Institute of Molecular Virology at Ulm University Medical Center-Germany and the  Gene Center at LMU München-Germany has found that the various SARS-CoV-2 variants of concern or VOCs are highly dependent on Interferon-inducible transmembrane proteins  or IFITMs for effective replication especially in iPSC-derived alveolar epithelial type II (iATII) cells, the target cells of SARS-CoV-2 in human lungs and effectively silencing IFITM2 using anti-IFITM2 antibodies inhibited the various SARS-CoV-2 VOCs.

The study findings were published on a preprint server and are currently being reviewed.

Since its first occurrence in Wuhan (China) in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has caused a devastating pandemic (1, 2). The reasons for the efficient spread of this coronavirus are not fully understood but clearly involve the ability to efficiently infect and propagate in human cells.

Viral entry depends on binding of the viral Spike (S) protein to the cellular angiotensin-converting enzyme (ACE) 2 receptor and proteolytic processing of the S precursor into the active S1 and S2 subunits (3–5). However, additional host factors may affect the efficiency of SARS-CoV-2 entry and play roles in viral transmission and pathogenesis (6).

We recently demonstrated that interferon-inducible transmembrane proteins (IFITMs 1, 2, and 3) are required for efficient SARS-CoV-2 infection (7).

This came as surprise since IFITMs are a family of IFN stimulated genes (ISGs) that are well-known to protect cells against infection by numerous viral pathogens including retro-, flavi-, influenza-, rhabdo-, filo- and bunyaviruses (3–5). Inhibitory effects have also been reported for highly pathogenic coronaviruses, including SARS-CoV-2 (8,9).

However, most evidence was obtained using pseudo-particles containing the S protein of SARS or MERS coronaviruses and/or cells that are not intrinsically permissve to this virus, artificially overexpress IFITM proteins and. Notably, it has been reported that the common cold coronavirus OC43 hijacks IFITM3 for efficient entry (10).

The antiviral mechanism of IFITMs is thought to involve alterations in the rigidity and curvature of the cellular membrane, affecting viruses in a broad, unspecific way (4, 5, 11). In contrast, the SARS-CoV-2 enhancing effect most likely involves specific interactions between the S protein and the N-terminal region of IFITMs, especially IFITM2 (7), suggesting that this pandemic viral pathogen hijacks IFITMs for efficient infection.

In accordance with this knock- down of endogenous IFITM2 expression in human lung cell lines strongly reduced viral entry and infectious virus production. In addition, IFITM2-derived peptides as well as an IFITM2-

targeting antibody protected gut organoids and cardiomyocytes against infection and cytopathic effects of SARS-CoV-2 (7).
In the initial study, IFITM dependency for efficient infection has only been demonstrated for an early European variant of SARS-CoV-2 isolated in the Netherlands in February 2020 (NL- 02-2020) (7).

Since then numerous variants have emerged. Some of them show increased transmission fitness and immune evasion and are thus referred to as “variants of concern” (VOCs). Currently, the WHO has categorized five SARS-CoV-2 variants as VOCs: B.1.1.7, B.1.351, P.1, B.1.617.2 and B.1.1.529.

The first four, referred to as Alpha, Beta, Gamma and Delta variants, have significantly spread in the human population. The latest (Omicron) variant contains a worrisome number of mutations (12).

However, it remains to be seen whether it might outcompete the Delta variant that currently dominates the pandemic and the Omicron variant was not yet Available for biological characterization. Compared to the NL-02-2020 isolate, all VOCs contain various alterations in their S proteins reported to enhance viral infectivity, transmissibility and pathogenicity by affecting ACE2 receptor affinity, proteolytic activation and susceptibility to neutralization (13–15).

Here, we examined whether current SARS-CoV-2 VOCs still require IFITM proteins for efficient replication in human lung cells.


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