Small clarifications questions for Cell Biology sections

[yemarshall]

Question to authors who wrote parts related to cell biology in Intro, Pathogenesis, & Therapeutics, @nilswellhausen @rays1987 @esell17 @jinhui2 @anskelly @davemai & if there's anyone else I missed. You guys know the cell biology more deeply than I do, so I didn't want to insert suggested changes myself (& also there are a lot of Pull Requests that relate to this so made an Issue instead of separate comments in Pull Requests). I do have some practice proofreading, so it may make sense for me to ask you these (but not correct them myself). I was (re-)reading the manuscript after having read the coronavirus biology reviews (already cited as references) and found a couple of places where I wasn't sure if there was an ambiguity or small-but-maybe-useful point missing with respect to the cell biology. Note that I haven't read cell biology on SARS-CoV-2, just some background cell biology on coronaviruses & looked up some basic cell biology (Molecular Biology of the Cell Textbook); that's another reason I prefer you guys check these questions & adjust text if there are any necessary clarifications.

1. From the coronavirus reviews Nature Reviews Microbiology 2016 [doi:10.1038/nrmicro.2016.81] and the 2015 Review [doi:10.1007/978-1-4939-2438-7_1], it seems that coronaviruses can fuse with either the endosomal membrane (?I'm guessing via receptor-mediated endocytosis?) or the host/cell/plasma membrane (?maybe also using a receptor? though this is unclear from figure in Nature article) -- this is what the texts seem to say & also the figure in Nature Reviews Microbiology maybe shows both options. I do not know if they mean that that some coronaviruses do one or the other or both/either entry strategies, and I do not know what is known for SARS-CoV-2. Basically, I noticed a couple of parts in the manuscript where this might need to be double-checked to make sure we are showing entry strategy(ies) which apply:
   • Section 1.2.3 Genome structure and replication. Sentence from earlier manuscript: "The viral membrane fuses with the endosomal membrane to release the viral genome into the host cytoplasm". Should this also include plasma membrane option? Also, regardless, before any possible adjustments, double-check whether referring to coronaviruses in general or a specific coronavirus or SARS-CoV-2.
   • Section 2.1.1 Primary Transmission and viral entry. Sentence from earlier manuscript: "The S protein is a highly glycosylated trimer that requires two proteolytic cleavage events, leading to substantial conformational changes, to achieve viral fusion with the host cell membrane [refs]." Though it may depend on which data is being referred to, should this also include fusion with endosomal membrane option or maybe this particular sentence is specific to just fusion with host cell membrane? Also, regardless, before any possible adjustments, double-check whether referring to coronaviruses in general or a specific coronavirus or SARS-CoV-2.
   • Section 4.5.1.1.1 Anticipated Mechanism for neutralizing antibodies (Section 4.5 Biological Drugs for COVID-19). Sentence "The S1 domain binds to host cell receptors while the S2 domain facilitates the fusion between the viral envelope and host cell membranes". Since this is geared towards SARS-CoV-2, I don't know what is known or anticipated for its cell biology (fusion with cell membrane or endosomal membrane or both/either or depends on what interested in), but I'm asking you to double-check since I don't know cell biology well enough & I haven't read these particular papers.
2. Section 4.2 Small Molecule Drugs for Targeting SARS-CoV-2. In the first paragraph there is a general description of a common virus replication cycle with excerpt "iv) biosynthesis, during which the viral genetic material enters the nucleus where it gets replicated;"; however, in the figure of the Nature Reviews Microbiology 2016 [doi:10.1038/nrmicro.2016.81] review article and also from the text (& maybe also review article 2015 [doi:10.1007/978-1-4939-2438-7_1]), I couldn't tell if the viral genetic material enters the nucleus in the case of coronaviruses or if there's some other pathway. This doesn't change that the first paragraph is describing a common virus replication cycle, but it might be useful to point out if there's a difference for coronaviruses (or SARS-CoV-2 if it's known?). I don't know if these questions make sense; if they don't, of course, you can ignore them! thanks!

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[nilswellhausen]

For 4.5.1.1.1: I think one need to distinguish between entry into cell and then entry into cytoplasm. Cell entry is receptor mediated endocytosis which requires receptor binding by S1 domain. Once in the endosome, the virus needs to leave the endosome to get into the cytoplasm for replication. That requires membrane fusion so that it can be released (mediated via S2). This paper here is a good resource for cell entry related data I think: https://www.pnas.org/content/early/2020/05/05/2003138117

[rando2]

I'm working on add some overview of the basic immunology (per #233) to the introduction, and I will link it here when I push it! I don't have a strong immunology background so I would feel much better if some of you don't mind reviewing it :)

[dziakj1]

Hello @rando2 ! Don't forget this overview of COVID-19 epidemiology in "Trends in Molecular Medicine" -- it might help you. https://www.cell.com/trends/molecular-medicine/pdf/S1471-4914(20)30065-4.pdf