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Very excited to share some of our lab’s work on SARS-CoV-2. This was a huge team effort – so many people in lab worked hard on this. This is still a preprint. We’ve found one possible reason why SARS-CoV-2 went pandemic and SARS-CoV didn’t. https://www.biorxiv.org/content/10.1101/2020.09.30.318311v1 Thread... 1/n
One difference between SARS-CoV-2 and SARS-CoV is the addition of 4 amino acids (PRRA) in the S1/S2 cleavage site making a furin cleavage site in spike. Furin cleavage of spike allows subsequent cleavage by TMPRSS2 and early entry into the cell bypassing the endosome. 2/n
If you passage SARS-CoV-2 in Vero E6 cells, it selects for a variety of deletions around the S1/S2 cleavage site insertion (∆Virus) but Vero cells don’t express TMPRSS2. 3/n
We can use WT and ∆Virus to show that WT is selected in cells expressing TMPRSS2, like those in the upper airway, but that ∆Virus is selected in cells that don’t express TMPRSS2 like Veros. 4/n
What’s going on? We show that SARS-CoV-2 entering via the endosome is restricted by IFITMs. When we inhibit IFITM restriction with drugs, WT and ∆Virus have similar fitness. 5/n
In cells which express TMPRSS2, it’s best to be cleaved by furin, enter early at the cell surface and avoid IFITMs. In cells which don’t express TMPRSS2, SARS2 has to enter via the endosome and it’s likely a disadvantage to be cleaved by furin as the virus is less stable. 6/n
Okay but does it really matter? Well in ferret transmission studies ∆Virus didn’t transmit when WT virus did! (Also seen by others in hamsters https://doi.org/10.1101/2020.08.25.266775.) We don’t see the ∆Virus transmitting between humans but we can find it at low levels within humans. 7/n
In all our pseudovirus assays, SARS-CoV spike acts like ∆Virus spike which means it has worse entry in the upper airway that SARS-CoV-2 and would be restricted by IFITMs. This is perhaps a virological reason why SARS-CoV-2 went pandemic and SARS-CoV didn’t. 8/n
Finally, although working in a pandemic was really difficult, we were lucky to be able to work! None of this work would have been possible without everyone who kept the building running and everyone in schools/nurseries who looked after our kids. @RFrise00 @wendybarclay11
