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Now, a new study published in the preprint server bioRxiv in August 2020 shows that under conditions resembling those in vivo, IFNs may promote efficient viral invasion instead. The virus behind the current COVID-19 pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is known to spread more efficiently than the earlier pathogenic coronaviruses, SARS-CoV, and MERS-CoV. However, the case fatality rate so far has been much lower, at 2% to 5%, compared to 10% in SARS and ~ 40% in MERS. Scientists think the virus is inhibited by interferons (IFNs), even more than the earlier viruses. In fact, IFNs are currently being used to reduce the severity of COVID-19. Now, a new study published in the preprint server bioRxiv* in August 2020 shows that under conditions resembling those in vivo, IFNs may promote efficient viral invasion instead.
What are IFITMs?
Interferon-induced transmembrane proteins (IFITMs 1, 2, and 3) are proteins that are considered to be inhibitory of a variety of viruses, including the SARS-CoVs. Most of the evidence for this has come from studies that used cells that overexpress these proteins and are infected by pseudoviruses. The investigators looked at innate immune effectors directed against SARS-CoV-2 entry into the target cells. Viral entry involves spike-mediated recognition of the host receptor, angiotensin-converting enzyme (ACE) 2, triggering an irreversible conformational change of the spike protein to its fusion form by proteolytic cleavage into S1 and S2 subunits. The cleaved protein fuses to the plasma membrane and gains entry to the cell. IFITMs are a family of IFN stimulated genes (ISGs) is known to prevent this fusion, in the case of influenza A viruses, rhabdoviruses, and HIV.
IFITM Overexpression Inhibits Pseudovirus S Binding
Previous work has shown that when these proteins are expressed at excessively high levels, pseudoparticles expressing the spike protein of SARS and MERS are unable to enter the host cell. The mechanism of inhibition might reduce the rigidity and curvature of the plasma membrane such that fusion cannot happen. While IFITM1 is only the plasma membrane, IFITM2 and 3 are localized on lysosomal membranes within the cell. Many scientists think that such viruses cannot replicate in cells where these proteins are expressed. However, some studies have shown that IFITMs can actually increase the intensity of infection with some human coronaviruses. At the same time, mutant IFITMs could enhance infection with many viruses from this family, including SARS. The current study shows that the overexpression of IFITMs specifically reduces the entry of SARS-CoV-2 spike-mediated pseudoparticles, by two orders of magnitude for IFITM2 and IFITM3 in particular, and less potently by IFITM1. Infectivity of these pseudoviruses was not reduced, however, and in fact, it was slightly increased in one case, since it may increase the rate at which the spike protein is built into the pseudovirus. The initial tests showed that both SARS-CoV and SARS-CoV-2 spike proteins expressed in pseudoviruses are inhibited efficiently by IFITMs, the first even more than the second. The mechanism of such inhibition appears to be via ubiquitination and palmitoylation. In all cases, they found that IFITMs reduce cell-to-cell fusion mediated by the spike-ACE2 binding. The depletion of these proteins led to a 3- to 7-fold increase in spike-mediated infection by all pseudoviral particles. Further testing in a cell line lacking IFITM expression showed that the number of S-ACE2 binding foci leaped upward by four- to ten-fold. These findings strongly imply that IFITM proteins are efficient inhibitors of SARS-CoV-2 S-mediated viral entry....
Study available as preprint at bioRxiv (August 18, 2020):
