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

Qian Zhang; Paul Bastard; Zhiyong Liu; Jérémie Le Pen; Marcela Moncada-Velez; Jie Chen; Masato Ogishi; Ira K D Sabli; Stephanie Hodeib; Cecilia Korol; Jérémie Rosain; Kaya Bilguvar; Junqiang Ye; Alexandre Bolze; Benedetta Bigio; Rui Yang; Andrés Augusto Arias; Qinhua Zhou; Yu Zhang; Fanny Onodi; Sarantis Korniotis; Léa Karpf; Quentin Philippot; Marwa Chbihi; Lucie Bonnet-Madin; Karim Dorgham; Nikaïa Smith; William M Schneider; Brandon S Razooky; Hans-Heinrich Hoffmann; Eleftherios Michailidis; Leen Moens; Ji Eun Han; Lazaro Lorenzo; Lucy Bizien; Philip Meade; Anna-Lena Neehus; Aileen Camille Ugurbil; Aurélien Corneau; Gaspard Kerner; Peng Zhang; Franck Rapaport; Yoann Seeleuthner; Jeremy Manry; Cecile Masson; Yohann Schmitt; Agatha Schlüter; Tom Le Voyer; Taushif Khan; András N Spaan; P. Bruijning-Verhagen

doi:10.1126/science.abd4570

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

Qian Zhang, Paul Bastard, Zhiyong Liu, Jérémie Le Pen, Marcela Moncada-Velez, Jie Chen, Masato Ogishi, Ira K D Sabli, Stephanie Hodeib, Cecilia Korol, Jérémie Rosain, Kaya Bilguvar, Junqiang Ye, Alexandre Bolze, Benedetta Bigio, Rui Yang, Andrés Augusto Arias, Qinhua Zhou, Yu Zhang, Fanny OnodiSarantis Korniotis, Léa Karpf, Quentin Philippot, Marwa Chbihi, Lucie Bonnet-Madin, Karim Dorgham, Nikaïa Smith, William M Schneider, Brandon S Razooky, Hans-Heinrich Hoffmann, Eleftherios Michailidis, Leen Moens, Ji Eun Han, Lazaro Lorenzo, Lucy Bizien, Philip Meade, Anna-Lena Neehus, Aileen Camille Ugurbil, Aurélien Corneau, Gaspard Kerner, Peng Zhang, Franck Rapaport, Yoann Seeleuthner, Jeremy Manry, Cecile Masson, Yohann Schmitt, Agatha Schlüter, Tom Le Voyer, Taushif Khan, András N Spaan, , P. Bruijning-Verhagen

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	eabd4570
Journal	Science
Volume	370
Issue number	6515
DOIs	https://doi.org/10.1126/science.abd4570
Publication status	Published - 23 Oct 2020

Keywords

Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Asymptomatic Infections
Betacoronavirus
COVID-19
Child
Child, Preschool
Coronavirus Infections/genetics
Female
Genetic Loci
Genetic Predisposition to Disease
Humans
Infant
Interferon Regulatory Factor-7/deficiency
Interferon Type I/immunology
Loss of Function Mutation
Male
Middle Aged
Pandemics
Pneumonia, Viral/genetics
Receptor, Interferon alpha-beta/deficiency
SARS-CoV-2
Toll-Like Receptor 3/deficiency
Young Adult

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science.abd4570Final published version, 1.32 MBLicence: CC BY

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Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., Ogishi, M., Sabli, I. K. D., Hodeib, S., Korol, C., Rosain, J., Bilguvar, K., Ye, J., Bolze, A., Bigio, B., Yang, R., Arias, A. A., Zhou, Q., Zhang, Y., ... Bruijning-Verhagen, P. (2020). Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science, 370(6515), Article eabd4570. https://doi.org/10.1126/science.abd4570

@article{997a770ec0a9433cac2341a98351228a,

title = "Inborn errors of type I IFN immunity in patients with life-threatening COVID-19",

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.",

keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Asymptomatic Infections, Betacoronavirus, COVID-19, Child, Child, Preschool, Coronavirus Infections/genetics, Female, Genetic Loci, Genetic Predisposition to Disease, Humans, Infant, Interferon Regulatory Factor-7/deficiency, Interferon Type I/immunology, Loss of Function Mutation, Male, Middle Aged, Pandemics, Pneumonia, Viral/genetics, Receptor, Interferon alpha-beta/deficiency, SARS-CoV-2, Toll-Like Receptor 3/deficiency, Young Adult",

author = "Qian Zhang and Paul Bastard and Zhiyong Liu and {Le Pen}, J{\'e}r{\'e}mie and Marcela Moncada-Velez and Jie Chen and Masato Ogishi and Sabli, {Ira K D} and Stephanie Hodeib and Cecilia Korol and J{\'e}r{\'e}mie Rosain and Kaya Bilguvar and Junqiang Ye and Alexandre Bolze and Benedetta Bigio and Rui Yang and Arias, {Andr{\'e}s Augusto} and Qinhua Zhou and Yu Zhang and Fanny Onodi and Sarantis Korniotis and L{\'e}a Karpf and Quentin Philippot and Marwa Chbihi and Lucie Bonnet-Madin and Karim Dorgham and Nika{\"i}a Smith and Schneider, {William M} and Razooky, {Brandon S} and Hans-Heinrich Hoffmann and Eleftherios Michailidis and Leen Moens and Han, {Ji Eun} and Lazaro Lorenzo and Lucy Bizien and Philip Meade and Anna-Lena Neehus and Ugurbil, {Aileen Camille} and Aur{\'e}lien Corneau and Gaspard Kerner and Peng Zhang and Franck Rapaport and Yoann Seeleuthner and Jeremy Manry and Cecile Masson and Yohann Schmitt and Agatha Schl{\"u}ter and {Le Voyer}, Tom and Taushif Khan and Spaan, {Andr{\'a}s N} and P. Bruijning-Verhagen",

note = "Funding Information: We thank the patients, their families, and healthy donors for placing their trust in us; Y. Nemirowskaya, D. Papandrea, M. Woollet, D. Liu, C. Rivalain, and C. Patissier for administrative assistance; A. Adeleye, D. Bacikova, E. McGrath Martinez, A. R. Soltis, K. Dobbs, J. Danielson, H. Matthews, and S. Weber for technical and other assistance; M. M. A. Ata and F. Al Ali for their contribution to VirScan experiments; S. Elledge (Brigham and Women's Hospital and Harvard Medical School, Boston, MA) for kindly providing the VirScan phage library used in this study; A. W. Ashbrook, the BSL3 manager of the Rice laboratory assistance; M. Lazzaro, Director of Immigration and Academic Appointments, for assistance; W. Chung, K. Kiryluk, S. O'Byrne, D. Pendrick, J. Williamson, C. Andrews, and M. Disco in the J.M. lab for assistance; M. Andreoni (Tor Vergata, Italy) for his clinical contribution; and A. Novelli (Bambino Ges{\`u} Hospital, Italy) for his collaboration. We thank the GEN-COVID Multicenter study (https://sites.google.com/dbm.unisi.it/gen-covid). This study used the high-performance computational resources of the National Institutes of Health (NIH) HPC Biowulf cluster (http://hpc.nih.gov) and the Office of Cyber Infrastructure and Computational Biology (OCICB) High Performance Computing (HPC) cluster at the National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD. The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the Uniformed Services University of the Health Sciences (USUHS) or the U.S. Department of Defense (DoD). Funding: 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 Solidarit{\'e} pour l'Enfance, the SCOR Corporate Foundation for Science, Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (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-morbidit{\`a}”), 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 M{\'e}dicale”), 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 Universit{\'e} 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 cient{\'i}ficas del ITER para colaborar en la lucha contra la COVID-19”). D.C.V. is supported by the Fonds de la recherche en sant{\'e} du Qu{\'e}bec 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). Publisher Copyright: {\textcopyright} 2020 American Association for the Advancement of Science. All rights reserved.",

year = "2020",

month = oct,

day = "23",

doi = "10.1126/science.abd4570",

language = "English",

volume = "370",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6515",

}

Zhang, Q, Bastard, P, Liu, Z, Le Pen, J, Moncada-Velez, M, Chen, J, Ogishi, M, Sabli, IKD, Hodeib, S, Korol, C, Rosain, J, Bilguvar, K, Ye, J, Bolze, A, Bigio, B, Yang, R, Arias, AA, Zhou, Q, Zhang, Y, Onodi, F, Korniotis, S, Karpf, L, Philippot, Q, Chbihi, M, Bonnet-Madin, L, Dorgham, K, Smith, N, Schneider, WM, Razooky, BS, Hoffmann, H-H, Michailidis, E, Moens, L, Han, JE, Lorenzo, L, Bizien, L, Meade, P, Neehus, A-L, Ugurbil, AC, Corneau, A, Kerner, G, Zhang, P, Rapaport, F, Seeleuthner, Y, Manry, J, Masson, C, Schmitt, Y, Schlüter, A, Le Voyer, T, Khan, T, Spaan, AN & Bruijning-Verhagen, P 2020, 'Inborn errors of type I IFN immunity in patients with life-threatening COVID-19', Science, vol. 370, no. 6515, eabd4570. https://doi.org/10.1126/science.abd4570

TY - JOUR

T1 - Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

AU - Zhang, Qian

AU - Bastard, Paul

AU - Liu, Zhiyong

AU - Le Pen, Jérémie

AU - Moncada-Velez, Marcela

AU - Chen, Jie

AU - Ogishi, Masato

AU - Sabli, Ira K D

AU - Hodeib, Stephanie

AU - Korol, Cecilia

AU - Rosain, Jérémie

AU - Bilguvar, Kaya

AU - Ye, Junqiang

AU - Bolze, Alexandre

AU - Bigio, Benedetta

AU - Yang, Rui

AU - Arias, Andrés Augusto

AU - Zhou, Qinhua

AU - Zhang, Yu

AU - Onodi, Fanny

AU - Korniotis, Sarantis

AU - Karpf, Léa

AU - Philippot, Quentin

AU - Chbihi, Marwa

AU - Bonnet-Madin, Lucie

AU - Dorgham, Karim

AU - Smith, Nikaïa

AU - Schneider, William M

AU - Razooky, Brandon S

AU - Hoffmann, Hans-Heinrich

AU - Michailidis, Eleftherios

AU - Moens, Leen

AU - Han, Ji Eun

AU - Lorenzo, Lazaro

AU - Bizien, Lucy

AU - Meade, Philip

AU - Neehus, Anna-Lena

AU - Ugurbil, Aileen Camille

AU - Corneau, Aurélien

AU - Kerner, Gaspard

AU - Zhang, Peng

AU - Rapaport, Franck

AU - Seeleuthner, Yoann

AU - Manry, Jeremy

AU - Masson, Cecile

AU - Schmitt, Yohann

AU - Schlüter, Agatha

AU - Le Voyer, Tom

AU - Khan, Taushif

AU - Spaan, András N

AU - Bruijning-Verhagen, P.

N1 - Funding Information: We thank the patients, their families, and healthy donors for placing their trust in us; Y. Nemirowskaya, D. Papandrea, M. Woollet, D. Liu, C. Rivalain, and C. Patissier for administrative assistance; A. Adeleye, D. Bacikova, E. McGrath Martinez, A. R. Soltis, K. Dobbs, J. Danielson, H. Matthews, and S. Weber for technical and other assistance; M. M. A. Ata and F. Al Ali for their contribution to VirScan experiments; S. Elledge (Brigham and Women's Hospital and Harvard Medical School, Boston, MA) for kindly providing the VirScan phage library used in this study; A. W. Ashbrook, the BSL3 manager of the Rice laboratory assistance; M. Lazzaro, Director of Immigration and Academic Appointments, for assistance; W. Chung, K. Kiryluk, S. O'Byrne, D. Pendrick, J. Williamson, C. Andrews, and M. Disco in the J.M. lab for assistance; M. Andreoni (Tor Vergata, Italy) for his clinical contribution; and A. Novelli (Bambino Gesù Hospital, Italy) for his collaboration. We thank the GEN-COVID Multicenter study (https://sites.google.com/dbm.unisi.it/gen-covid). This study used the high-performance computational resources of the National Institutes of Health (NIH) HPC Biowulf cluster (http://hpc.nih.gov) and the Office of Cyber Infrastructure and Computational Biology (OCICB) High Performance Computing (HPC) cluster at the National Institute of Allergy and Infectious Diseases (NIAID), Bethesda, MD. The opinions and assertions expressed herein are those of the authors and are not to be construed as reflecting the views of the Uniformed Services University of the Health Sciences (USUHS) or the U.S. Department of Defense (DoD). Funding: 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). Publisher Copyright: © 2020 American Association for the Advancement of Science. All rights reserved.

PY - 2020/10/23

Y1 - 2020/10/23

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - Asymptomatic Infections

KW - Betacoronavirus

KW - COVID-19

KW - Child

KW - Child, Preschool

KW - Coronavirus Infections/genetics

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Humans

KW - Infant

KW - Interferon Regulatory Factor-7/deficiency

KW - Interferon Type I/immunology

KW - Loss of Function Mutation

KW - Male

KW - Middle Aged

KW - Pandemics

KW - Pneumonia, Viral/genetics

KW - Receptor, Interferon alpha-beta/deficiency

KW - SARS-CoV-2

KW - Toll-Like Receptor 3/deficiency

KW - Young Adult

UR - http://www.scopus.com/inward/record.url?scp=85094120212&partnerID=8YFLogxK

U2 - 10.1126/science.abd4570

DO - 10.1126/science.abd4570

M3 - Article

C2 - 32972995

SN - 0036-8075

VL - 370

JO - Science

JF - Science

IS - 6515

M1 - eabd4570

ER -

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

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