Thread by @StuartTurville

Images of SARS-CoV-2 cultures often tell us a thousand words. Here we have the Omicron lineage XBB.1.5 growing in two engineered cells. Both equally express ACE2 and TMPRSS2. Visually this sums up our journey into the complicated entry pathway of Omicron lineages......1/

2/ To cut a long story very short, the difference in the two cell types and why one looks like a Delta infection (but is XBB.1.5) is the pool of ACE2 that is present in the cell with obvious replication revealed by cell-cell fusion. This pool of ACE2 is resistant TMPRSS2 action

3/ Beautiful work by Stefan Polhmann's team in 2014 on SARS CoV-1 lead us to look at the dynamics between ACE2 and TMPRSS2 on SARS CoV-2 entry. pubmed.ncbi.nlm.nih.gov/24227843/

4/ In this work, Stefan's team observed SARS-CoV-1 entry was facilitated by TMPRSS2 cleaving not only the Spike glycoprotein but also the receptor ACE2. When we looked at this for SARS CoV-2..... across all isolates that covered the pandemic, we saw something interesting.

5/ Whilst early SARS CoV-2 entered in a manner like SARS CoV-1... TMPRSS2 cleaved ACE2 facilitated entry only for SARS CoV-2 that was prior to Omicron. What defined Omicron entry, was progressive attenuation in settings where ACE2 was cleaved by TMPRSS2. It was a off switch....

6/ For latter TMPRSS2 activation of Spike. Omicron's simply did not like pools of ACE2 that were cleaved.

7/ So what does this mean? It is well established that Omicrons are attenuated in the Lung but do well in other tissues. Why and how would the above observations fit with this?

8/ The body has two pools of ACE2 that do a very different function. The first is embedded in the well known angiotensin system. Here the neck of ACE2 needs to be exposed to be regulated by either TMPRSS2 or ADAM17 cleavage. One signals ACE2 to stay, the other to be shed.

9/ The second function of ACE2 is as a chaperone for proteins that transport amino acids. A large pool of ACE2 does this in the small intestine complexed to a protein called B0AT1/SLC6A19. In this setting we would support ACE2 to be TMPRSS2 cleavage resistant.

10/ So how does this explain what Omicrons are up to and how they enter.... A tissue site where the neck of ACE2 can be cleaved by TMPRSS2 (eg. Lung) turns off the ability for Omicrons to latter use TMPRSS2. This is the fundamental change from Delta to Omicron lineages to date.

11/ To really get our heads scratching. Here is the pre-print that maps the biology of this. Stefan Pohlmann's work in 2014 on SARS CoV-1 was key here! biorxiv.org/content/10.110…