Kavli Affiliate: Jean Laurent Casanova
| Authors: 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 de Cevins, Mickaël M Ménager, Francesca Luca, Roger Pique-Regi, Giovanna Barba-Spaeth, Stefano Pietropaoli, Olivier Schwartz, Geert Leroux-Roels, Cheuk-Kwong Lee, Kathy Leung, Joseph T.K. Wu, Joseph Sriyal Malik Peiris, Roberto Bruzzone, Laurent Abel, Jean-Laurent Casanova, Sophie A Valkenburg, Darragh A Duffy, Etienne Patin, Maxime Rotival and Lluis Quintana-Murci
| Summary:
Abstract Humans display vast clinical variability upon SARS-CoV-2 infection, partly due to genetic and immunological factors. However, the magnitude of population differences in immune responses to SARS-CoV-2 and the mechanisms underlying such variation remain unknown. Here we report single-cell RNA-sequencing data for peripheral blood mononuclear cells from 222 healthy donors of various ancestries stimulated with SARS-CoV-2 or influenza A virus. We show that SARS-CoV-2 induces a weaker, but more heterogeneous interferon-stimulated gene activity than influenza A virus, and a unique pro-inflammatory signature in myeloid cells. We observe marked population differences in transcriptional responses to viral exposure that reflect environmentally induced cellular heterogeneity, as illustrated by higher rates of cytomegalovirus infection, affecting lymphoid cells, in African-descent individuals. Expression quantitative trait loci and mediation analyses reveal a broad effect of cell proportions on population differences in immune responses, with genetic variants having a narrower but stronger effect on specific loci. Additionally, natural selection has increased immune response differentiation across populations, particularly for variants associated with SARS-CoV-2 responses in East Asians. We document the cellular and molecular mechanisms through which Neanderthal introgression has altered immune functions, such as its impact on the myeloid response in Europeans. Finally, colocalization analyses reveal an overlap between the genetic architecture of immune responses to SARS-CoV-2 and COVID-19 severity. Collectively, these findings suggest that adaptive evolution targeting immunity has also contributed to current disparities in COVID-19 risk. Competing Interest Statement The authors have declared no competing interest.