TMPRSS2 activation of Omicron lineage Spike glycoproteins is regulated by TMPRSS2 cleavage of ACE2, 2023, Anupriya Aggarwal et al

Abstract
Continued high levels spread of SARS-CoV-2 globally enabled accumulation of changes within the Spike glycoprotein, leading to resistance to neutralising antibodies and concomitant changes to entry requirements that increased viral transmission fitness.

Herein, we demonstrate a significant change in ACE2 and TMPRSS2 use by primary SARS-CoV-2 isolates that occurred upon arrival of Omicron lineages. Mechanistically we show this shift to be a function of two distinct ACE2 pools based on cleavage or non-cleavage of ACE2 by TMPRSS2 activity.

In engineered cells overexpressing ACE2 and TMPRSS2, ACE2 was cleaved by TMPRSS2 and this led to either augmentation or progressive attenuation of pre-Omicron and Omicron lineages, respectfully. In contrast, TMPRSS2 resistant ACE2 restored infectivity across all Omicron lineages through enabling ACE2 binding that facilitated TMPRSS2 spike activation.

Therefore, our data support the tropism shift of Omicron lineages to be a function of evolution towards the use of uncleaved pools of ACE2 with the latter consistent with its role as a chaperone for many tissue specific amino acid transport proteins.

https://www.biorxiv.org/content/10.1101/2023.09.22.558930v1

 

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Omicron has changed how the virus enters cells. Normally, the virus uses a cellular door called ACE2 and a key called TMPRSS2 to get in. Omicron has learned to pick the lock differently, using another form of ACE2 that's resistant to TMPRSS2.

This allows the variant to enter cells more efficiently, making it better at spreading. It's like a burglar finding a new, faster way to jimmy a lock, making it harder to defend against the intrusion.

This indicates a shift in viral tropism, likely as a function of an evolutionary drive toward exploiting an uncleaved pool of ACE2. This adaptational nuance in receptor utilization poses implications for both transmission dynamics and neutralizing antibody efficacy.