Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

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dc.contributor.authorZhang, Qian
dc.contributor.authorBastard, Paul
dc.contributor.authorLiu, Zhiyong
dc.contributor.authorLe Pen, Jeremie
dc.contributor.authorMoncada-Velez, Marcela
dc.contributor.authorChen, Jie
dc.contributor.authorOgishi, Masato
dc.date.accessioned2024-02-23T14:26:08Z
dc.date.available2024-02-23T14:26:08Z
dc.date.issued2020
dc.departmentNEÜen_US
dc.description.abstractClinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3-and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.en_US
dc.description.sponsorshipHoward Hughes Medical Institute; Rockefeller University; St. Giles Foundation; NIH [P01AI138398-S1, 2U19AI111825, R01AI09170710S1]; National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program [UL1 TR001866]; Mercatus Center at George Mason University - National Human Genome Research Institute (NHGRI) [UM1HG006504, U24HG008956]; French National Research Agency (ANR) under the Investments for the Future program [ANR-10-IAHU-01, ANR-10-LABX-62-IBEID]; French Foundation for Medical Research (FRM) [EQU201903007798]; FRM; ANR GENCOVID project [ANRS-COV05]; Square Foundation, Grandir-Fonds de Solidarite pour l'Enfance; SCOR Corporate Foundation for Science; University of Paris; Inserm; REACTing consortium; French Ministry of Health [PHRC 20-0424]; Regione Lombardia, Italy (project Risposta immune in pazienti con COVID-19 e comorbidita); Intramural Research Program of the NIAID, NIH [ANR-10-LABX-62-IBEID]; Fondation pour la Recherche Medicale [FRM-EQU202003010193]; Agence Nationale de la Recherche (ANR FLASH COVID project IDISCOVR); (Fondation pour la Recherche Medicale), University of Paris [RACPL20FIR01-COVID-SOUL]; FWO Vlaanderen; FWO [G0C8517N -GOB5120N]; Agence Nationale de la Recherche [ANR-17-CE15-0003, ANR-17-CE150003-01]; Universite de Paris PLAN D'URGENCE [COVID19]; French Ministry of Research; UKRI Future Leaders Fellowship [MR/S032304/1]; Elite Journals Program at King Saud University [PEJP-16-107, UL1TR001873]; George Mason University Fast Grant; G. Harold and Leila Y. Mathers Charitable Foundation; European Molecular Biology Organization Long-Term Fellowship [ALTF 380-2018]; European Union [824110, COVID-19/PID12342]; Instituto de Salud Carlos III [COV20_01333, COV20_01334]; Spanish Ministry of Science and Innovation; European Regional Development Fund-European Social Fund -FEDER-FSE [RTC-2017-6471-1]; AEI/FEDER; Cabildo Insular de Tenerife [CGIEU0000219140]; (Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19); Fonds de la recherche en sante du Quebec clinician-scientist scholar program; Foundation Bettencourt Schueller - Netherlands Organization for Health Research and Development (ZonMw) [NWO-vici 91819627, U19AI135972, U19AI142733, R35 HL135834, HHSN272201800048C]; DoD [W81XWH-20-1-0270]; DARPA project [HR0011-19-2-0020]; CRIP (Center for Research on Influenza Pathogenesis); NIAID [75N93019C00051]; JPB Foundation; Open Philanthropy Project [2020-215611(5384)]; Sidra Medicine; Biomedical Advanced Research and Development Authority [HHSO10201600031C]; Agence Nationale de la Recherche (ANR) [ANR-17-CE15-0003] Funding Source: Agence Nationale de la Recherche (ANR); UKRI [MR/S032304/1] Funding Source: UKRIen_US
dc.description.sponsorshipThis work was supported by a generous donation from the Fisher Center for Alzheimer's Research Foundation. The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the NIH (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), the NIH Clinical and Translational Science Award (CTSA) program (UL1 TR001866), 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 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, ANRS-COV05, the Square Foundation, Grandir-Fonds de Solidarite pour l'Enfance, the SCOR Corporate Foundation for Science, Institut National de la Sante et de la Recherche Medicale (INSERM), the University of Paris. The French COVID Cohort study group was sponsored by Inserm and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). Regione Lombardia, Italy (project Risposta immune in pazienti con COVID-19 e comorbidita), and the Intramural Research Program of the NIAID, NIH. The laboratory of Genomes & Cell Biology of Disease is supported by Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID), the Fondation pour la Recherche Medicale (grant FRM-EQU202003010193), the Agence Nationale de la Recherche (ANR FLASH COVID project IDISCOVR cofounded by the Fondation pour la Recherche Medicale), University of Paris (Plan de Soutien Covid-19: RACPL20FIR01-COVID-SOUL). I.M. is a senior clinical investigator with the FWO Vlaanderen; I.M. and L.M. are supported by FWO G0C8517N -GOB5120N. The VS team was supported by Agence Nationale de la Recherche (ANR-17-CE15-0003, ANR-17-CE150003-01) and by Universite de Paris PLAN D'URGENCE COVID19. L.K. was supported by a fellowship from the French Ministry of Research. V.S.-S. is supported by a UKRI Future Leaders Fellowship (MR/S032304/1). S.Z.A.-M. is supported by the Elite Journals Program at King Saud University through grant no. PEJP-16-107. The J.M. laboratory is supported by Columbia University COVID biobank and grant no. UL1TR001873. Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, and R01AI09170710S1; a George Mason University Fast Grant; and the G. Harold and Leila Y. Mathers Charitable Foundation. J.L.P. is supported by a European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). Work at the Neurometabolic Diseases Laboratory received funding from the European Union's Horizon 2020 research and innovation program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342) to A.P., and Roche and Illumina Covid Match Funds to M.G.. C.R.G. and colleagues are supported by Instituto de Salud Carlos III (COV20_01333 and COV20_01334), Spanish Ministry of Science and Innovation, with the funding of European Regional Development Fund-European Social Fund -FEDER-FSE; (RTC-2017-6471-1; AEI/FEDER, UE), and Cabildo Insular de Tenerife (CGIEU0000219140 and Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19). D.C.V.; r r is supported by the Fonds de la recherche en sante du Quebec clinician-scientist scholar program. H.S. is adjunct faculty at the University of Pennsylvania. A.-L.N. was supported by the Foundation Bettencourt Schueller. The Amsterdam UMC Covid-19 Biobank was funded by the Netherlands Organization for Health Research and Development (ZonMw, NWO-vici 91819627), The Corona Research Fund (Amsterdam UMC), Dr. J. C. Vaillantfonds, and Amsterdam UMC. Work on COVID-19 at the A.G.-S. laboratory is partly supported by NIH supplements to grants U19AI135972, U19AI142733, and R35 HL135834, and to contract HHSN272201800048C, by a DoD supplement to grant W81XWH-20-1-0270, by DARPA project HR0011-19-2-0020, by CRIP (Center for Research on Influenza Pathogenesis), a NIAID funded Center of Excellence for Influenza Research and Surveillance (CEIRS, contract HHSN272201400008C), by an NIAID funded Collaborative Influenza Vaccine Innovation Center (SEM-CIVIC, contract 75N93019C00051) and by the generous support of the JPB Foundation, the Open Philanthropy Project (research grant 2020-215611(5384)) and anonymous donors. The Virscan analysis presented in fig. S11 was performed with financial support from Sidra Medicine. J.R.H. is supported by Biomedical Advanced Research and Development Authority under Contract (HHSO10201600031C).en_US
dc.identifier.doi10.1126/science.abd4570
dc.identifier.issn0036-8075
dc.identifier.issn1095-9203
dc.identifier.issue6515en_US
dc.identifier.pmid32972995en_US
dc.identifier.scopus2-s2.0-85094120212en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1126/science.abd4570
dc.identifier.urihttps://hdl.handle.net/20.500.12452/14066
dc.identifier.volume370en_US
dc.identifier.wosWOS:000581077200034en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmer Assoc Advancement Scienceen_US
dc.relation.ispartofScienceen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleInborn errors of type I IFN immunity in patients with life-threatening COVID-19en_US
dc.typeArticleen_US

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