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Reviews of "SARS-CoV-2 requires acidic pH to infect cells"

Reviewers: Francisco Sobrino (Center for Molecular Biology Severo Ochoa) | 📗📗📗📗◻️ • Andreas Herrmann (Freie Universität Berlin) | 📘📘📘📘📘

Published onJul 21, 2022
Reviews of "SARS-CoV-2 requires acidic pH to infect cells"
key-enterThis Pub is a Review of
SARS-CoV-2 requires acidic pH to infect cells

ABSTRACTSARS-CoV-2 cell entry starts with membrane attachment and ends with spike-protein (S) catalyzed membrane fusion depending on two cleavage steps, one usually by furin in producing cells and the second by TMPRSS2 on target cells. Endosomal cathepsins can carry out both. Using real-time 3D single virion tracking, we show fusion and genome penetration requires virion exposure to an acidic milieu of pH 6.2-6.8, even when furin and TMPRSS2 cleavages have occurred. We detect the sequential steps of S1-fragment dissociation, fusion, and content release from the cell surface in TMPRRS2 overexpressing cells only when exposed to acidic pH. We define a key role of an acidic environment for successful infection, found in endosomal compartments and at the surface of TMPRSS2 expressing cells in the acidic milieu of the nasal cavity.Significance StatementInfection by SARS-CoV-2 depends upon the S large spike protein decorating the virions and is responsible for receptor engagement and subsequent fusion of viral and cellular membranes allowing release of virion contents into the cell. Using new single particle imaging tools, to visualize and track the successive steps from virion attachment to fusion, combined with chemical and genetic perturbations of the cells, we provide the first direct evidence for the cellular uptake routes of productive infection in multiple cell types and their dependence on proteolysis of S by cell surface or endosomal proteases. We show that fusion and content release always require the acidic environment from endosomes, preceded by liberation of the S1 fragment which depends on ACE2 receptor engagement.One sentence summaryDetailed molecular snapshots of the productive infectious entry pathway of SARS-CoV-2 into cells

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Summary of Reviews: This paper investigates the role of acidic environments in cells for SARS-CoV-2 infection susceptibility using 3D single virion tracking microscopy. Reviewers find the study reliable but emphasize the need to validate the observations for the entry of authentic SARS-CoV-2 virus.

Reviewer 1 (Francisco Sobrino) | 📗📗📗📗◻️

Reviewer 2 (Andreas Hermann) | 📘📘📘📘📘

RR:C19 Strength of Evidence Scale Key

📕 ◻️◻️◻️◻️ = Misleading

📙📙 ◻️◻️◻️ = Not Informative

📒📒📒 ◻️◻️ = Potentially Informative

📗📗📗📗◻️ = Reliable

📘📘📘📘📘 = Strong

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