Thread by @vipintukur

Key findings on #Omicron’s characteristics:

1-Omicron spike binds ACE2 better than Delta.

2-Both Omicron & Delta replicate similarly in nasal cell cultures

3-However, in airway cells high in TMPRSS2 there was significant impairment for Omicron. 1/

4-Omicron has altered preference for cell entry towards a TMPRSS2 *independent* pathway that involves engulfing of virus by endocytosis rather than fusion of the virus with the cell directly (TMPRSS2 *dependent*). 2/

5-Consistent with impaired use of #TMPRSS2, the Omicron spike was inefficiently cleaved

This came as a surprise because Omicron has 3 mutations around the polybasic cleavage site (S1/S2). 3/

6-A second striking and surprising finding related to spike cleavage impairment was that the Omicron spike was poor at promoting cells to fuse together, a process called cell-cell fusion or syncytium formation. (The result is that infected cell foci are smaller in the assay) 4/

7-Inability to fuse cells may contribute to reduced severity by limiting local spread of infection and possibly also inflammation. 5/

Conclusions:

1-Omicron, with its array of mutations, has dramatically different biological behaviour.

2-Whilst the increased ACE2 binding affinity and immune evasion can be explained by RBD mutations, the determinant of spike cleavage impairment is unknown. 6/

Some unanswered Qs:

1-Which came first, increased ACE2 binding or impaired spike cleavage & shift away from TMPRSS2+ cells?

2-Or did they occur in different viruses within a single chronically infected host before a within host recombination event? 7/

nature.com/articles/s4158…

Here is the detailed 🧵 by @GuptaR_lab 👇

https://twitter.com/GuptaR_lab/status/1489005418735099906