Inborn errors of type I IFN immunity in patients

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  • dc.contributor.author Zhang, Qian
  • dc.contributor.author Gut, Marta
  • dc.contributor.author Casanova, Jean-Laurent
  • dc.date.accessioned 2022-07-08T06:40:00Z
  • dc.date.available 2022-07-08T06:40:00Z
  • dc.date.issued 2020
  • dc.description.abstract Clinical 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.
  • dc.description.sponsorship This 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 Solidarité pour l’Enfance, the SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (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 co-morbidità”), 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 Médicale”), 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-CE15-0003-01) and by Université 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 R01AI091707-10S1; 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 científicas del ITER para colaborar en la lucha contra la COVID-19”). D.C.V. is supported by the Fonds de la recherche en santé du Québec 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).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients. Science. 2020 Oct 23; 370(6515): eabd4570. DOI: 10.1126/science.abd4570
  • dc.identifier.doi http://dx.doi.org/10.1126/science.abd4570
  • dc.identifier.issn 0036-8075
  • dc.identifier.uri http://hdl.handle.net/10230/53699
  • dc.language.iso eng
  • dc.publisher American Association for the Advancement of Science (AAAS)
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/824110
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-83039-R
  • dc.rights Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. This is an open-access article distributed under the terms of the Creative Commons Attribution license, http://creativecommons.org/licenses/by/4.0/ which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Asymptomatic Infections
  • dc.subject.other COVID-19
  • dc.subject.other Coronavirus Infections
  • dc.subject.other Interferon Regulatory Factor-7
  • dc.subject.other Loss of Function Mutation
  • dc.title Inborn errors of type I IFN immunity in patients
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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