A global effort to dissect the human genetic basis of resistance to SARS-CoV-2 infection

Abstract

SARS-CoV-2 infections display tremendous interindividual variability, ranging from asymptomatic infections to life-threatening disease. Inborn errors of, and autoantibodies directed against, type I interferons (IFNs) account for about 20% of critical COVID-19 cases among SARS-CoV-2-infected individuals. By contrast, the genetic and immunological determinants of resistance to infection per se remain unknown. Following the discovery that autosomal recessive deficiency in the DARC chemokine receptor confers resistance to Plasmodium vivax, autosomal recessive deficiencies of chemokine receptor 5 (CCR5) and the enzyme FUT2 were shown to underlie resistance to HIV-1 and noroviruses, respectively. Along the same lines, we propose a strategy for identifying, recruiting, and genetically analyzing individuals who are naturally resistant to SARS-CoV-2 infection.The Laboratory of Human Genetics of Infectious Diseases is supported by the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the French National Research Agency (ANR) under the Investments for the Future program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS-COV05, the Fondation du Souffle, the Square Foundation, Grandir - Fonds de solidarité pour l’enfance, the SCOR Corporate Foundation for Science, the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, Institut National de la Santé et de la Recherche Médicale (INSERM), and the University of Paris. E.A. is supported by research grants from the European Commission’s Horizon 2020 research and innovation program (IMMUNAID, grant no. 779295, CURE, grant no. 767015 and TO_AITION grant no. 848146) and the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). C.O.F. is supported in part by the Science Foundation Ireland COVID-19 Program. G.N. is supported by a grant awarded to Regione Lazio (Research Group Projects 2020) no. A0375-2020-36663, GecoBiomark. A.P. is supported in part by the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342) and the CERCA Program/Generalitat de Catalunya. H.S. is supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. A.S. is supported in part by the European Union’s Horizon 2020 research and innovation program (Marie Sklodowska-Curie grant no. 789645)