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

Kapil Gupta*, Christine Toelzer, Maia Kavanagh Williamson, Deborah K Shoemark, A Oliveira, Andrew D Davidson, Abdulaziz M Almuqrin, Oskar Staufer, Sathish Yadav Kadapalakere, Ufuk Borucu, Frederic Garzoni, Daniel J Fitzgerald, Joachim Pius Spatz, Adrian J Mulholland, Andrew D Davidson, Christiane H Berger-Schaffitzel, Imre Berger*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

15 Citations (Scopus)
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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.
Original languageEnglish
Article number222
Number of pages12
JournalNature Communications
Volume13
Issue number1
DOIs
Publication statusPublished - 11 Jan 2022

Bibliographical note

Funding Information:
We thank all members of the Berger and Schaffitzel teams as well as Robin Shattock (Imperial College, UK) and Adam Finn (Bristol UNCOVER Group and Children’s Vaccine Centre, Bristol Medical School) for their assistance and advice. We thank Simon Burbidge, Thomas Batstone and Matt Williams for computation infrastructure support. We would like to thank the Advanced Computing Research Centre (ACRC) at the University of Bristol for access to BlueCryo, BlueCrystal Phase 4 and BlueGEM, and the UK HECBioSim for access to the UK supercomputer, ARCHER. We are particularly grateful to Thiru Thangarajah (Genscript) for early access to Genscript’s cPass™ SARS-CoV-2 Neutralization Antibody Detection/Surrogate Virus Neutralization Test Kit (L00847). We thank Sebastian Fabritz and the Core Facility for Mass Spectrometry at the Max Planck Institute for Medical Research for their support on MS measurements. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. This research received support from the Elizabeth Blackwell Institute for Health Research and the EPSRC Impact Acceleration Account EP/R511663/1, University of Bristol, from Bris-SynBio a BBSRC/EPSRC Research Centre for synthetic biology at the University of Bristol (BB/L01386X/1) (I.B., C.S., A.J.M., D.K.S., and A.S.F.O.) and from the BBSRC (BB/P000940/1) (C.S. and I.B.). This work received generous support from the Oracle Higher Education and Research program to enable cryo-EM data processing using Oracle’s high-performance public cloud infrastructure (https://cloud.oracle.com/en_US/ cloud-infrastructure) and the EPSRC through a COVID-19 project award via HECBioSim to access ARCHER (A.J.M.). We acknowledge support and assistance by the Wolfson Bioimaging Facility and the GW4 Facility for High-Resolution Electron Cryo-Microscopy funded by the Wellcome Trust (202904/Z/16/Z and 206181/Z/17/Z) and BBSRC (BB/R000484/1). The authors are grateful to University of Bristol’s Alumni and Friends, which funded the ImageXpress Pico Imaging System. O.S. acknowledges support from the Elisabeth Muerer Foundation, the Max Planck School Matter to Life and the Heidelberg Biosciences International Graduate School. J.S. is the Weston Visiting Professor at the Weizmann Institute of Science, part of the excellence cluster CellNetworks at Heidelberg University and acknowledges funding from the European Research Council (ERC, contract no. 294852), SynAd and the MaxSynBio Consortium, funded by the Federal Ministry of Education and Research of Germany and the Max Planck Society, from the SFB 1129 and Project 240245660-SFB1129 P15 of the German Research Foundation (DFG) and from the Volkswagen Stiftung (priority call “Life?”). A.D.D. and D.A.M. are supported by the United States Food and Drug Administration (HHSF223201510104C) and UK Research and Innovation/Medical Research Council (MRC) (MR/V027506/1). M.K.W is supported by MRC grants MR/R020566/1 and MR/ V027506/1 (awarded to A.D.D). A.J.M. is supported by the British Society for Antimicrobial Chemotherapy (BSAC-COVID-30) and the EPSRC (EP/M022609/1, CCP-BioSim). I.B. acknowledges support from the EPSRC Innovative Future Vaccine Manufacturing and Research Hub (EP/R013764/1). C.S. and I.B. are Investigators of the Wellcome Trust (210701/Z/18/Z; 106115/Z/14/Z).

Publisher Copyright:
© 2022, The Author(s).

Structured keywords

  • Bristol BioDesign Institute
  • Max Planck Bristol
  • UNCOVER
  • Covid19

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