Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses

Yann Aquino (1, 2) , Aurélie Bisiaux (1) , Zhi Li (1) , Mary O’neill (1) , Javier Mendoza-Revilla (1) , Sarah Hélène Merkling (3) , Gaspard Kerner (1) , Milena Hasan (4) , Valentina Libri (4) , Vincent Bondet (5) , Nikaïa Smith (6) , Camille de Cevins (7, 6) , Mickaël Ménager (7, 6) , Francesca Luca (8, 9) , Roger Pique-Regi (8) , Giovanna Barba-Spaeth (10) , Stefano Pietropaoli (10) , Olivier Schwartz (11) , Geert Leroux-Roels (12, 13) , Cheuk-Kwong Lee (14) , Kathy Leung (15) , Joseph T.K. Wu (15) , Malik Peiris (15) , Roberto Bruzzone (15) , Laurent Abel (16, 17, 18, 6) , Jean-Laurent Casanova (16, 17, 18, 19, 6) , Sophie Valkenburg (15, 20) , Darragh Duffy (5, 21) , Etienne Patin (1) , Maxime Rotival (1) , Lluis Quintana-Murci (1, 22)

1 Génétique Evolutive Humaine - Human Evolutionary Genetics
2 Collège Doctoral
3 IVI - Interactions Virus-Insectes - Insect-Virus Interactions
4 UTechS CB - Cytometrie et Biomarqueurs – Cytometry and Biomarkers
5 Immunologie Translationnelle - Translational Immunology lab
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 Equipe Inserm U1163 - Inflammatory Responses and Transcriptomic Networks in diseases
8 Wayne State University [Detroit]
9 University of Rome "Tor Vergeta"
10 Virologie Structurale - Structural Virology
11 CNRS-UMR3569 - Virus et Immunité - Virus and immunity
12 UGENT - Universiteit Gent = Ghent University
13 Ghent University Hospital
14 Hong Kong Red Cross Blood Transfusion Service
15 HKU - The University of Hong Kong
16 Rockefeller University [New York]
17 CHU Necker - Enfants Malades [AP-HP]
18 Equipe Inserm U1163 - Human genetics of infectious diseases: Complex predisposition
19 HHMI - Howard Hughes Medical Institute
20 University of Melbourne
21 HKSTP - Hong Kong Science and Technology Parks Corporation
22 Collège de France - Chaire Génomique humaine et évolution

Humans display vast clinical variability upon SARS-CoV-2 infection 1–3 , partly due to genetic and immunological factors 4 . 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.

Domains: Life Sciences [q-bio]

Yann Aquino, Aurélie Bisiaux, Zhi Li, Mary O’neill, Javier Mendoza-Revilla, et al.. Environmental and genetic drivers of population differences in SARS-CoV-2 immune responses. 2023. ⟨pasteur-03913748⟩