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Environmental variation and genetic diversity contribute to population differences in immune responses to SARS-CoV-2 and COVID-19 risk

Genes & Immunity (2023)Cite this article

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The COVID-19 pandemic has brought to light considerable clinical variation among individuals infected with SARS-CoV-2, ranging from asymptomatic cases to fatal outcome [1]. Factors influencing this variability include advanced age, male sex, comorbidities, and human genetics [1, 2]. Specifically, inborn errors of or auto-antibodies against type I interferons (IFNs) have been identified as strong contributors to the severity of COVID-19 pneumonia [2]. Additionally, genome-wide association studies (GWAS) involving over 200,000 cases and 3 million controls have pinpointed 51 distinct loci associated with susceptibility to infection by SARS-CoV-2 or severity of COVID-19, underscoring the important role of human genetic factors in the pathophysiology of the disease [3].

In searching for differences in immune response across populations, we found 3389 genes displaying population differences in expression in the basal state, and 898 and 652 genes displaying differential responses between populations after stimulation with SARS-CoV-2 and IAV, respectively. Basic differences in cellular composition accounted for a substantial portion (up to 50%) of population differences in gene expression, with the most significant impact on NK cells. Furthermore, our study identified latent cytomegalovirus (CMV) infection as an important predictor of cellular heterogeneity, with CMV being most prevalent in African-descent individuals. CMV serostatus was associated with higher proportions of memory-like NK and CD8+ EMRA T cells, revealing how variation in environmental exposures, like CMV infection, can contribute to population differences in responses to SARS-CoV-2 through changes in blood cell composition.

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Fig. 1: Factors driving variation in immune responses to SARS-CoV-2 and COVID-19 risk.

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Acknowledgements

The Human Evolutionary Genetics Laboratory is supported by the Institut Pasteur, the Collège de France, the Centre Nationale de la Recherche Scientifique (CNRS), the Agence Nationale de la Recherche (ANR) grants COVID-19-POPCELL (ANR-21-CO14-0003-01), POPCELL-REG (ANR-22-CE12-0030-01) and COVIFERON (ANR-21-RHUS-0008), the EU HORIZON-HLTH-2021-DISEASE-04-07 grant UNDINE (no. 101057100), the French Government’s Investissement d’Avenir program, Laboratoires d’Excellence “Integrative Biology of Emerging Infectious Diseases” (ANR-10- LABX-62-IBEID) and “Milieu Intérieur” (ANR-10-LABX-69-01), the Fondation pour la Recherche Médicale (Equipe FRM DEQ20180339214), the Fondation Allianz-Institut de France, and the Fondation de France (no. 00106080).

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  1. Institut Pasteur, Université Paris Cité, CNRS UMR2000, Human Evolutionary Genetics Unit, Paris, France

    Maxime Rotival & Lluis Quintana-Murci

  2. Human Genomics and Evolution, Collège de France, Paris, France

    Lluis Quintana-Murci

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  1. Maxime Rotival
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  2. Lluis Quintana-Murci
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MR and LQM wrote the manuscript.

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Correspondence to Lluis Quintana-Murci.

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Rotival, M., Quintana-Murci, L. Environmental variation and genetic diversity contribute to population differences in immune responses to SARS-CoV-2 and COVID-19 risk. Genes Immun (2023). https://doi.org/10.1038/s41435-023-00249-0

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