Structural basis for cell-type specific evolution of viral fitness by SARS-CoV-2

Gupta, Kapil; Toelzer, Christine; Williamson, Maia Kavanagh; Shoemark, Deborah K.; Oliveira, A. Sofia F.; Matthews, David A.; Almuqrin, Abdulaziz; Staufer, Oskar; Yadav, Sathish K.N.; Borucu, Ufuk; Garzoni, Frederic; Fitzgerald, Daniel; Spatz, Joachim; Mulholland, Adrian J.; Davidson, Andrew D.; Schaffitzel, Christiane; Berger, Imre

As the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants which is of particular concern due to their potential for increased transmissibility and pathology. In addition to this entrenched variant diversity in circulation, RNA viruses can also display genetic diversity within single infected hosts with co-existing viral variants evolving differently in distinct cell types. The BriSΔ variant, originally identified as a viral subpopulation by passaging SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike glycoprotein an eight amino-acid deletion encompassing the furin recognition motif and S1/S2 cleavage site. Here, we elucidate the structure, function and molecular dynamics of this variant spike providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 receptor binding and infectivity of this SARS-CoV-2 variant. Moreover, our study reveals long-range allosteric communication between functional regions within the spike that differ in wild-type and deletion variant. Our results support a view of SARS-CoV-2 probing multiple evolutionary trajectories in distinct cell types within the same infected host.