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Dissecting human population variation in single-cell responses to SARS-CoV-2. 2023
Yann Aquino, and
Aurélie Bisiaux, and
Zhi Li, and
Mary O'Neill, and
Javier Mendoza-Revilla, and
Sarah Hélène Merkling, and
Gaspard Kerner, and
Milena Hasan, and
Valentina Libri, and
Vincent Bondet, and
Nikaïa Smith, and
Camille de Cevins, and
Mickaël Ménager, and
Francesca Luca, and
Roger Pique-Regi, and
Giovanna Barba-Spaeth, and
Stefano Pietropaoli, and
Olivier Schwartz, and
Geert Leroux-Roels, and
Cheuk-Kwong Lee, and
Kathy Leung, and
Joseph T Wu, and
Malik Peiris, and
Roberto Bruzzone, and
Laurent Abel, and
Jean-Laurent Casanova, and
Sophie A Valkenburg, and
Darragh Duffy, and
Etienne Patin, and
Maxime Rotival, and
Lluis Quintana-Murci
Human Evolutionary Genetics Unit, Institut Pasteur, Université Paris Cité, CNRS UMR2000, Paris, France.
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.
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