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Review 2: "SARS-CoV-2 spike downregulates tetherin to enhance viral spread"

This preprint demonstrates that host cells employ a known pathway in which interferon-induced tetherin “tethers” SARS-CoV-2 to the inner plasma membrane to restrict viral exit. Reviewers recognize the data as reliable with minor revisions needed.

Published onAug 13, 2021
Review 2: "SARS-CoV-2 spike downregulates tetherin to enhance viral spread"

RR:C19 Evidence Scale rating by reviewer:

  • Strong. The main study claims are very well-justified by the data and analytic methods used. There is little room for doubt that the study produced has very similar results and conclusions as compared with the hypothetical ideal study. The study’s main claims should be considered conclusive and actionable without reservation.

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Review:

The authors investigated the possible role of the cellular protein tetherin in modulating an infection by SARS-CoV-2.  The studies were based on the observation that tetherin appears to inhibit the release of a number of enveloped RNA viruses including coronaviruses HCoV-229E and SARS-CoV-1. In the characterized viral infections, tetherin appears to bind to the encapsidated virus and prevent its release from infected cells.  The viruses appear to have acquired the ability to disrupt this cellular defense mechanism by typically downregulating the production of tetherin.  

Based on prior work, the authors tested whether SARS-CoV-2 also dysregulated tetherin by analyzing the role of tetherin in three different cell lines, including HeLa cells, A549 cells, and T84 cells.  Most of their work was in HeLa cells, while A549 cells were tested primarily because they are transformed respiratory epithelial cells.  The reason for using T84 cells was not described in the manuscript—a rationale should be given. After demonstrating that tetherin localization is dysregulated by infection of SARS-CoV-2, the authors then used the HeLa cell model system with a tetherin knockout to show that tetherin did, in fact, reduce the yield of virus generated from infected cells—in agreement with the studies done with other RNA viruses.  Finally, the authors used a series of expression vectors to determine which of the viral genes was responsible for the dysregulation of tetherin.  The authors found that unlike the situation with the other coronaviruses, which used ORF7a to repress tetherin, SARS-CoV-2 appeared to utilize the spike protein to dysregulate the function of tetherin.  While the majority of the data presented in this manuscript is quite robust, the data with respect to the spike protein is less convincing with respect to the repression of tetherin.  Nevertheless, it appears that SARS-CoV-2 is capable of dysregulating tetherin in infected cells primarily through modulation of tetherin localization by spike protein. 

The authors concluded that SARS-CoV-2 affects tetherin by reducing the protein levels, but their data is arguably more consistent with an effect on tetherin reorganization from the plasma membrane to internal sites.  The authors note this but do not really explore how the reorganization of tetherin might result in a reduction in the yield of infectious viruses.  The studies described here leave two important questions unanswered.  First, what is the basis for the difference between ORF7a in the viruses in which ORF7a causes repression compared to SARS-CoV-2?  Second, what is the basis and mechanism for the reorganization of tetherin by the spike protein?  Presumably, these questions are beyond the scope of this manuscript but are important to better understand the molecular biology of infection by SARS-CoV-2. 

Overall the studies described in this manuscript are a valuable addition to the literature on host-virus interactions by SARS-CoV-2.  The results clearly demonstrate that SARS-CoV-2 disrupts the normal organization of tetherin in the plasma membrane, that this disruption is associated with spike protein, and that the consequence of tetherin disruption is a reduction in the yield of infectious SARS-CoV-2 virus.  While the results will be primarily interesting to researchers studying SARS-CoV-2, they will also be of interest to scientists interested in the role of tetherin in controlling virus yield by enveloped viruses in general.  Finally, as the authors point out, the virus tetherin interaction may eventually be targeted therapeutically to reduce the severity of infection by SARS-CoV-2 or other viruses. 

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