matfax
commented
4 years ago Summary
In this study, Xinling Wang et al. showed that SARS-CoV-2 uses a secondary cell-cell fusion path that is not mediated by ACE2. They compared in vitro 293T/ACE2, Huh7, HeLa, MT-2, and A3.01 cell lines for their infection ability from SARS-CoV, and SARS-CoV-2. They further analyzed the ACE2 expression in MT-2, A3.01, and 293T/ACE2 cell lines. The relative ACE2 expression of MT-2 and A3.01 cells was below 0.0001 when compared to 293T/ACE2 cells. Despite the low ACE2 expression of these MT-2 and A3.01 cells, SARS-CoV-2 showed a significant increase of N gene expression in these cultures over time. Fluorescence images confirmed that the propagation included a cell-cell fusion mechanism. 24 hours after infection, 23.11% of MT-2 cells were infected. In order to verify the role of the spike protein (S) and cell receptors in the fusion mechanism, the authors used their own EK1 peptide which has shown to inhibit pan-coronavirus fusion. A high concentration of 40 μM of EK1 could inhibit fusion to some degree. This study confirms the previous theories that ACE2 is not the only protein that provides SARS-CoV-2 cell entry. CD147 could be the responsible receptor for the T cell infection since it has a high expression on T cells.
Comment
This study is concise but significant in its findings. If ACE2 is not the only entry receptor for SARS-CoV-2, then this might explain why single-drug ACE2-entry-targeting trials (e.g., for protease inhibitors) don't show as significant effectiveness as some researchers might have expected previously. Leukocytopenia was determined to have a high correlation to the severity index of COVID-19 patients. There may be a link between both. However, lymphocytopenia was already known from SARS-CoV. A CypA-mediated CD147-channeled entry was also known from SARS-CoV [10.1086/427811]. A mutation in the S protein of SARS-CoV-2 could be responsible for the significantly enhanced T cell entry when compared to SARS-CoV. That is because SARS-CoV was known to use not the S protein but the N protein for CypA-mediated cell invasion. Unfortunately, the EK1 experiment doesn't tell much because of high deviations and a missing indication regarding concentration-dependency. In their EK1 study, they showed the concentration-dependent knockout effect on SARS-CoV-2 [10.1038/s41422-020-0305-x], so why didn't they use a knockout concentration to verify that it could be completely inhibited? This information is crucial to verify that it is indeed the S protein and not also the N protein of SARS-CoV-2 that is involved in the T cell invasion mechanism. Moreover, I could neither verify that EK1 inhibits only the S protein and not the N protein invasion as well. Is there a trivial explanation for that?
I have an undergraduate science degree. Please read it critically.
Title: SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion
General Information
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Link: https://doi.org/10.1038/s41423-020-0424-9
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Citation: doi:10.1038/s41423-020-0424-9
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