Thread by @sigallab

We looked at whether #SARSCoV2 attenuates after extensive evolution in an immunosuppressed individual.

Submitted to medRxiv and available on sigallab.net while it gets screened. Bottom line is no.

It evolved to cause more cell death and cell fusion.

Starting with Omicron BA.1, there was a drop in severe disease because of increasing immunity and changes to the virus itself which decrease lower respiratory tract infection. The hope is that because the virus evolved extensively, it became milder, better adapted to us.

We tested the hypothesis that extensive evolution attenuates SARS-CoV-2 by checking viruses from a long-term infection from a person with immunosuppression because of advanced HIV disease.

We made movies of cellular infection, and this is what it looks like with no infection:

The virus does some of its damage by making cells in the lower respiratory tract fuse and die, leading to inflammation.

In these movies taken in cell culture over 50 hours, cell nuclei are fluorescent (shown in red).

Here we infected with virus from early on in the infection:

Note some fusion and death happens at the end.

Here we infected with virus that has been evolving for 6 months in the individual. Note the much higher frequency of fusion and death:

We quantified the results using automated image analysis and compared infection induced cell fusion and fold-change in cell number (higher means more cell division and less death) to Omicron BA.1 and ancestral SARS-CoV-2.

We saw that the early, day 6 post-diagnosis (D6) isolated virus was similar to BA.1. However, the later isolate from day 190 of infection (D190) behaved more like ancestral SARS-CoV-2.

It's not simple because early virus was attenuated. However, by parameters we measured, it became less attenuated, showing that long-term evolution does not always lead to attenuation.

Therefore, the next major variant, if it comes, may not necessarily be as mild as Omicron.

I want to thank @GilLustig and @YashiG24 for leading the project and the rest of the team at @AHRI_News, @CAPRISAOfficial, @krisp_news, @ceri_news, especially @ProfAbdoolKarim