Human SARS-CoV-2 challenge uncovers differences in local and systemic cellular responses associated with protection from infection and distinct infection states

Despite the rapid global COVID-19 research effort, our understanding of how and why some people go on to develop an infection upon SARS-CoV-2 viral exposure, whilst others do not, remains limited. The world’s first Human COVID-19 Challenge Study offers a unique opportunity to delineate the differences in the cellular dynamics between abortive, transient, and sustained infection groups. Matched nasopharyngeal and blood samples were collected at 6-7 timepoints (pre-infection to 28 days post-infection) from 16 healthy seronegative individuals inoculated with pre-alpha SARS-CoV-2 and processed for multi-omic single cell analysis (n=181). Our data revealed dozens of rapid and highly dynamic changes in cell type proportions and cellular response states in the epithelium and immune cells associated with specific timepoints and infection status. We observed an interferon response in blood that preceded that in the nasopharynx, with a rapid local infiltration of immune cells in transiently infected participants. Several early anti-viral ciliated cell responses were also identified, with non-productive infections in the resident T cells and macrophages. A high expression of <italic>HLA-DQA2</italic> pre-inoculation was associated with protection. Lastly, we described a subpopulation of acutely activated T cells, clonally expanded and carrying convergent SARS-CoV-2 TCR motifs. Overall, our detailed time series data (covid19cellatlas.org) can serve as a “Rosetta stone” for epithelial and immune cell responses and reveals early dynamic responses associated with protection from infection, providing insights to further aid treatment and vaccine design.

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Publication Details

Published
2024-09-14
DOI
https://doi.org/10.1183/13993003.congress-2024.oa1891
Primary Topic
SARS-CoV-2 and COVID-19 Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Human SARS-CoV-2 challenge uncovers differences in local and systemic cellular responses associated with protection from infection and distinct infection states

Kaylee B. Worlock, Puja Mehta, Alex Mann, Maria Goeppert Mayer et al.
SARS-CoV-2 and COVID-19 Research
article

Human SARS-CoV-2 challenge uncovers differences in local and systemic cellular responses associated with protection from infection and distinct infection states

Kaylee B. Worlock, Puja Mehta, Alex Mann, Maria Goeppert Mayer, Jessica Allen-Hyttinen, Maximillian Woodall, Mahdad Noursadeghi, Christopher Chiu, Dinithi Sumanaweera, Anna Wilbrey-Clark, Andrew Catchpole, Lira Mamanova, Lisa M. Dratva, Sarah Amalia Teichmann, Lorenz Kretschmer, Liam Bolt, Robert S. Heyderman, Rik G.H. Lindeboom, Marko Nikolić, Benny Chain, Elena Prigmore, Helen R. Wagstaffe, Jacqueline Marcia Boccacino, Josephine L. Barnes, Laura Richardson, Claire M. Smith, Leo Swadling, Andreas Mayer, Alison Boyers, Sam M. Janes, Rasa Elmentaite, Muzlifah A. Haniffa, Masahiro Yoshida, Rachel C. Chambers, Rakeshlal Kapuge, Mariya Kalinova, Samuel Ellis, David R. Scobie, Krzysztof Polański, Vitor H. Teixeira, Kerstin B. Meyer, Waradon Sungnak, Ni Huang, Ben Kilingley
article en

Abstract

Despite the rapid global COVID-19 research effort, our understanding of how and why some people go on to develop an infection upon SARS-CoV-2 viral exposure, whilst others do not, remains limited. The world’s first Human COVID-19 Challenge Study offers a unique opportunity to delineate the differences in the cellular dynamics between abortive, transient, and sustained infection groups. Matched nasopharyngeal and blood samples were collected at 6-7 timepoints (pre-infection to 28 days post-infection) from 16 healthy seronegative individuals inoculated with pre-alpha SARS-CoV-2 and processed for multi-omic single cell analysis (n=181). Our data revealed dozens of rapid and highly dynamic changes in cell type proportions and cellular response states in the epithelium and immune cells associated with specific timepoints and infection status. We observed an interferon response in blood that preceded that in the nasopharynx, with a rapid local infiltration of immune cells in transiently infected participants. Several early anti-viral ciliated cell responses were also identified, with non-productive infections in the resident T cells and macrophages. A high expression of <italic>HLA-DQA2</italic> pre-inoculation was associated with protection. Lastly, we described a subpopulation of acutely activated T cells, clonally expanded and carrying convergent SARS-CoV-2 TCR motifs. Overall, our detailed time series data (covid19cellatlas.org) can serve as a “Rosetta stone” for epithelial and immune cell responses and reveals early dynamic responses associated with protection from infection, providing insights to further aid treatment and vaccine design.

University College Hospital (GB), Great Ormond Street Hospital (GB), Wellcome Sanger Institute (GB), hVIVO (United Kingdom) (GB), Institute of Infection and Immunity (CA), University College London (GB), Imperial College London (GB)
Biotechnology and Biological Sciences Research Council
Good health and well-being
Openalex Percentile: Top 75%
SARS-CoV-2 and COVID-19 Research
DOISourceOpenAlex
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