Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2

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

doi:10.1038/s41467-021-27881-6

Abstract

As the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants with increased transmissibility and pathology. In addition to this entrenched diversity, 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 from SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike an eight amino-acid deletion encompassing a furin recognition motif and S1/S2 cleavage site. We elucidate the structure, function and molecular dynamics of this spike providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 receptor binding and infectivity of this SARS-CoV-2 variant. Our results reveal long-range allosteric communication between functional domains that differ in the wild-type and the deletion variant and support a view of SARS-CoV-2 probing multiple evolutionary trajectories in distinct cell types within the same infected host.

Highlights

As the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants with increased transmissibility and pathology
The differences in the infectivity of the WT and BriSΔ viruses were compared on Vero E6, Vero E6/TMPRSS2, Caco-2, Caco-2-ACE2 and Calu-3 cells using a range of virus dilutions for infection (Fig. 1b–f)
Our results using Vero E6/TMPRSS2 cells are similar to those of Zhu et al[18] comparing the replication of WT SARSCoV-2 and a virus (Sdel) containing a 7 amino acid deletion encompassing the furin cleavage site but differ from those based on a competition assay between the WT and ΔPRRA viruses, which infected Vero E6/TMPRSS2 cells well[19]

Summary

Introduction

As the global burden of SARS-CoV-2 infections escalates, so does the evolution of viral variants with increased transmissibility and pathology. The BriSΔ variant, originally identified as a viral subpopulation from SARS-CoV-2 isolate hCoV-19/England/02/2020, comprises in the spike an eight amino-acid deletion encompassing a furin recognition motif and S1/S2 cleavage site. Function and molecular dynamics of this spike providing mechanistic insight into how the deletion correlates to viral cell tropism, ACE2 receptor binding and infectivity of this SARS-CoV-2 variant. We dissect the structure, dynamics and mechanism of the BriSΔ deletion variant S we identified, to gain insight into how diversification of the virus by elimination of a loop-region comprising the furin recognition motif and S1/S2 cleavage site impacts viral cell tropism, infectivity, spike protein stability and receptor binding, revealing molecular communication between functional regions within the spike glycoprotein allowing SARSCoV-2 to evolve intra-host diversity in distinct cell types

Methods

Results

Conclusion