Human SARS-CoV-2 challenge uncovers local and systemic response dynamics

Rik G. H. Lindeboom (), Kaylee B. Worlock, Lisa M. Dratva, Masahiro Yoshida, David Scobie, Helen R. Wagstaffe, Laura Richardson, Anna Wilbrey-Clark, Josephine L. Barnes, Lorenz Kretschmer, Krzysztof Polanski, Jessica Allen-Hyttinen, Puja Mehta, Dinithi Sumanaweera, Jacqueline M. Boccacino, Waradon Sungnak, Rasa Elmentaite, Ni Huang, Lira Mamanova, Rakesh Kapuge, Liam Bolt, Elena Prigmore, Ben Killingley, Mariya Kalinova, Maria Mayer, Alison Boyers, Alex Mann, Leo Swadling, Maximillian N. J. Woodall, Samuel Ellis, Claire M. Smith, Vitor H. Teixeira, Sam M. Janes, Rachel C. Chambers, Muzlifah Haniffa, Andrew Catchpole, Robert Heyderman, Mahdad Noursadeghi, Benny Chain, Andreas Mayer, Kerstin B. Meyer, Christopher Chiu, Marko Z. Nikolić () and Sarah A. Teichmann ()
Additional contact information
Rik G. H. Lindeboom: Wellcome Genome Campus
Kaylee B. Worlock: University College London
Lisa M. Dratva: Wellcome Genome Campus
Masahiro Yoshida: University College London
David Scobie: University College London
Helen R. Wagstaffe: Imperial College London
Laura Richardson: Wellcome Genome Campus
Anna Wilbrey-Clark: Wellcome Genome Campus
Josephine L. Barnes: University College London
Lorenz Kretschmer: Wellcome Genome Campus
Krzysztof Polanski: Wellcome Genome Campus
Jessica Allen-Hyttinen: University College London
Puja Mehta: University College London
Dinithi Sumanaweera: Wellcome Genome Campus
Jacqueline M. Boccacino: Wellcome Genome Campus
Waradon Sungnak: Wellcome Genome Campus
Rasa Elmentaite: Wellcome Genome Campus
Ni Huang: Wellcome Genome Campus
Lira Mamanova: Wellcome Genome Campus
Rakesh Kapuge: Wellcome Genome Campus
Liam Bolt: Wellcome Genome Campus
Elena Prigmore: Wellcome Genome Campus
Ben Killingley: University College London Hospital
Mariya Kalinova: hVIVO
Maria Mayer: hVIVO
Alison Boyers: hVIVO
Alex Mann: hVIVO
Leo Swadling: University College London
Maximillian N. J. Woodall: UCL Great Ormond Street Institute of Child Health
Samuel Ellis: UCL Great Ormond Street Institute of Child Health
Claire M. Smith: UCL Great Ormond Street Institute of Child Health
Vitor H. Teixeira: University College London
Sam M. Janes: University College London
Rachel C. Chambers: University College London
Muzlifah Haniffa: Wellcome Genome Campus
Andrew Catchpole: hVIVO
Robert Heyderman: University College London
Mahdad Noursadeghi: University College London
Benny Chain: University College London
Andreas Mayer: University College London
Kerstin B. Meyer: Wellcome Genome Campus
Christopher Chiu: Imperial College London
Marko Z. Nikolić: University College London
Sarah A. Teichmann: Wellcome Genome Campus

Nature, 2024, vol. 631, issue 8019, 189-198

Abstract: Abstract The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited1. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.

Date: 2024
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DOI: 10.1038/s41586-024-07575-x

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