Dissecting human population variation in single-cell responses to SARS-CoV-2

Yann Aquino, Aurélie Bisiaux, Zhi Li, Mary O’Neill, Javier Mendoza-Revilla, Sarah Hélène Merkling, Gaspard Kerner, Milena Hasan, Valentina Libri, Vincent Bondet, Nikaïa Smith, Camille Cevins, Mickaël Ménager, Francesca Luca, Roger Pique-Regi, Giovanna Barba-Spaeth, Stefano Pietropaoli, Olivier Schwartz, Geert Leroux-Roels, Cheuk-Kwong Lee, Kathy Leung, Joseph T. Wu, Malik Peiris, Roberto Bruzzone, Laurent Abel, Jean-Laurent Casanova, Sophie A. Valkenburg, Darragh Duffy, Etienne Patin, Maxime Rotival () and Lluis Quintana-Murci ()
Additional contact information
Yann Aquino: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Aurélie Bisiaux: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Zhi Li: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Mary O’Neill: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Javier Mendoza-Revilla: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Sarah Hélène Merkling: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Gaspard Kerner: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Milena Hasan: Institut Pasteur, Université Paris Cité
Valentina Libri: Institut Pasteur, Université Paris Cité
Vincent Bondet: Institut Pasteur, Université Paris Cité
Nikaïa Smith: Institut Pasteur, Université Paris Cité
Camille Cevins: Université Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR1163
Mickaël Ménager: Université Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR1163
Francesca Luca: Wayne State University
Roger Pique-Regi: Wayne State University
Giovanna Barba-Spaeth: Institut Pasteur, Université Paris Cité, CNRS UMR3569
Stefano Pietropaoli: Institut Pasteur, Université Paris Cité, CNRS UMR3569
Olivier Schwartz: Institut Pasteur, Université Paris Cité, CNRS UMR3569
Geert Leroux-Roels: Ghent University and University Hospital
Cheuk-Kwong Lee: Hong Kong Red Cross Blood Transfusion Service, Hospital Authority
Kathy Leung: The University of Hong Kong
Joseph T. Wu: The University of Hong Kong
Malik Peiris: The University of Hong Kong
Roberto Bruzzone: The University of Hong Kong
Laurent Abel: The Rockefeller University
Jean-Laurent Casanova: The Rockefeller University
Sophie A. Valkenburg: The University of Hong Kong
Darragh Duffy: Institut Pasteur, Université Paris Cité
Etienne Patin: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Maxime Rotival: Institut Pasteur, Université Paris Cité, CNRS UMR2000
Lluis Quintana-Murci: Institut Pasteur, Université Paris Cité, CNRS UMR2000

Nature, 2023, vol. 621, issue 7977, 120-128

Abstract: Abstract Humans display substantial interindividual clinical variability after SARS-CoV-2 infection1–3, the genetic and immunological basis of which has begun to be deciphered4. However, the extent and drivers of population differences in immune responses to SARS-CoV-2 remain unclear. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells—from 222 healthy donors of diverse ancestries—that were stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces weaker, but more heterogeneous, interferon-stimulated gene activity compared with influenza A virus, and a unique pro-inflammatory signature in myeloid cells. Transcriptional responses to viruses display marked population differences, primarily driven by changes in cell abundance including increased lymphoid differentiation associated with latent cytomegalovirus infection. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell composition on population disparities in immune responses, with genetic variants exerting a strong effect on specific loci. Furthermore, we show that natural selection has increased population differences in immune responses, particularly for variants associated with SARS-CoV-2 response in East Asians, and document the cellular and molecular mechanisms by which Neanderthal introgression has altered immune functions, such as the response of myeloid cells to viruses. Finally, colocalization and transcriptome-wide association analyses reveal an overlap between the genetic basis of immune responses to SARS-CoV-2 and COVID-19 severity, providing insights into the factors contributing to current disparities in COVID-19 risk.

Date: 2023
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DOI: 10.1038/s41586-023-06422-9

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