Thread by @__ice9

@farid__jalali @SWICU_Rays @NG20194 @abledoc Most likely just cell-cell fusion or overrunning them with virions, given type II pneumocytes are often directly adjacent to capillary squamous endothelial cells and pericytes.

The pericytes may even be the primary endothelial subpopulation at risk.

biorxiv.org/content/10.110…

@farid__jalali @SWICU_Rays @NG20194 @abledoc This article does not sufficiently address the other ways in which platelets contribute to the disease state, but does discuss various endothelial subpopulations involved, including viral infection of both endothelial squamous cells and pericytes:

nature.com/articles/s4157…

@farid__jalali @SWICU_Rays @NG20194 @abledoc Pericytes are present in relatively low proportions, however, and vascular-associated smooth muscle cell populations are also known to express ACE2 to some degree. Most likely all endothelial subpopulations are susceptible, to varying extents.

See also:
nejm.org/doi/full/10.10…

@farid__jalali @SWICU_Rays @NG20194 @abledoc SARS-CoV-2 Spike is primed by cleaving S1/S2, usually by furin before the virion leaves the original host cell.
sciencedirect.com/science/articl…

A second cut at S2' deploys the fusion protein. For cell-cell fusion, a serine protease at the cell surface does it.
nature.com/articles/s4146…

@farid__jalali @SWICU_Rays @NG20194 @abledoc TMPRSS2 is a suitable membrane-associated serine protease, though it is possible that others may also be able to cleave S2' in other tissues. In Calu-3 cells, though, only TMPRSS2 seems to work.
biorxiv.org/content/10.110…

@farid__jalali @SWICU_Rays @NG20194 @abledoc If S1/S2 is not primed, entry may not be possible at the cell surface.

The virion is pulled into a vesicle by endocytosis of the bound ACE2 receptor, entering an endosome where cathepsins are present.

They cleave S1/S2:
cell.com/iscience/pdf/S…

And S2':
ncbi.nlm.nih.gov/pmc/articles/P…

@farid__jalali @SWICU_Rays @NG20194 @abledoc Cells expressing TMPRSS2 or another suitable membrane serine protease are susceptible to cell-cell fusion when an adjacent infected cell expresses Spike at its membrane.

Cells that do not express such a protease are not, and can only use the endosomal route with free virions.

@farid__jalali @SWICU_Rays @NG20194 @abledoc Expression of TMPRSS2 also allows a 'shortcut' path for infection by free virions vs. the slower endosomal route.

The reduced latency to infection allows the virus to spread quickly between TMPRSS2+ (or equivalent) cells, even though they are a minority.

https://twitter.com/__ice9/status/1286654571083902977?s=20

@farid__jalali @SWICU_Rays @NG20194 @abledoc This also has implications for antivirals.

Drugs that block endosomal acidification (cathepsins are acid hydrolase enzymes) block endosomal entry.

Drugs that block membrane-associated serine proteases block 'shortcut' cell surface entry and cell-cell fusion.

@farid__jalali @SWICU_Rays @NG20194 @abledoc And here is a whole thread on that, regarding entry inhibitors:

https://twitter.com/__ice9/status/1289171228708618241?s=20

Wish nafamostat were approved in the U.S. Looks extremely useful.