TY - JOUR
T1 - Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
AU - Amsterdam UMC Covid-19 Biobank
AU - COVID Human Genetic Effort
AU - NIAID-USUHS/TAGC COVID Immunity Group
AU - COVID Clinicians
AU - Imagine COVID Group
AU - COVID-STORM Clinicians
AU - French COVID Cohort Study Group
AU - CoV-Contact Cohort
AU - Zhang, Qian
AU - Liu, Zhiyong
AU - Moncada-Velez, Marcela
AU - Chen, Jie
AU - Ogishi, Masato
AU - Bigio, Benedetta
AU - Yang, Rui
AU - Arias, Andrés Augusto
AU - Zhou, Qinhua
AU - Han, Ji Eun
AU - Ugurbil, Aileen Camille
AU - Zhang, Peng
AU - Rapaport, Franck
AU - Li, Juan
AU - Spaan, András N.
AU - Boisson, Bertrand
AU - Boisson-Dupuis, Stéphanie
AU - Bustamante, Jacinta
AU - Puel, Anne
AU - Ciancanelli, Michael J.
AU - Zhang, Shen Ying
AU - Béziat, Vivien
AU - Jouanguy, Emmanuelle
AU - Abel, Laurent
AU - Cobat, Aurélie
AU - Casanova, Jean Laurent
AU - Bastard, Paul
AU - Korol, Cecilia
AU - Rosain, Jérémie
AU - Philippot, Quentin
AU - Chbihi, Marwa
AU - Lorenzo, Lazaro
AU - Bizien, Lucy
AU - Neehus, Anna Lena
AU - Kerner, Gaspard
AU - Seeleuthner, Yoann
AU - Manry, Jeremy
AU - Le Voyer, Tom
AU - Boisson, Bertrand
AU - Boisson-Dupuis, Stéphanie
AU - Bustamante, Jacinta
AU - van Agtmael, Michiel
AU - Sigaloff, Kim
AU - Bos, Lieuwe
AU - Girbes, Armand
AU - Thoral, Patrick
AU - Bugiani, Marianna
AU - de Jong, Menno D.
AU - Teunissen, Charlotte
AU - Wouters, Dorien
AU - le Pen, J. rémie
AU - Sabli, Ira K. D.
AU - Hodeib, Stephanie
AU - Bilguvar, Kaya
AU - Ye, Junqiang
AU - Bolze, Alexandre
AU - Zhang, Yu
AU - Onodi, Fanny
AU - Korniotis, Sarantis
AU - Karpf, L. a
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 - Meade, Philip
AU - Corneau, Aurélien
AU - Masson, Cecile
AU - van de Beek, Diederik
AU - Hovius, Joppe W. R.
AU - Schultz, Marcus J.
AU - Horn, Johanna
AU - Hollmann, Markus W.
AU - Schmitt, Yohann
AU - Schlüter, Agatha
AU - Khan, Taushif
AU - Stilma, Willemke
N1 - Amsterdam UMC Covid-19 Biobank Michiel van Agtmael1, Anna Geke Algera2, Frank van Baarle2, Diane Bax3, Martijn Beudel4, Harm Jan Bogaard5, Marije Bomers1, Lieuwe Bos2, Michela Botta2, Justin de Brabander6, Godelieve de Bree6, Matthijs C. Brouwer4, Sanne de Bruin2, Marianna Bugiani7, Esther Bulle2, Osoul Chouchane1, Alex Cloherty3, Paul Elbers2, Lucas Fleuren2, Suzanne Geerlings1, Bart Geerts8, Theo Geijtenbeek9, Armand Girbes2, Bram Goorhuis1, Martin P. Grobusch1, Florianne Hafkamp9, Laura Hagens2, Jorg Hamann10, Vanessa Harris1, Robert Hemke11, Sabine M. Hermans1, Leo Heunks2, Markus W. Hollmann8, Janneke Horn2, Joppe W. Hovius1, Menno D. de Jong12, Rutger Koning4, Niels van Mourik2, Jeaninne Nellen1, Frederique Paulus2, Edgar Peters1, Tom van der Poll1, Benedikt Preckel8, Jan M. Prins1, Jorinde Raasveld2, Tom Reijnders1, Michiel Schinkel1, Marcus J. Schultz2, Alex Schuurman13, Kim Sigaloff1, Marry Smit2, Cornelis S. Stijnis1, Willemke Stilma2, Charlotte Teunissen14, Patrick Thoral2, Anissa Tsonas2, Marc van der Valk1, Denise Veelo8, Alexander P.J. Vlaar15, Heder de Vries2, Michèle van Vugt1, W. Joost Wiersinga1, Dorien Wouters16, A. H. (Koos) Zwinderman17, Diederik van de Beek4*
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 - 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 - Toll-Like Receptor 3/deficiency
KW - Young Adult
UR - http://www.scopus.com/inward/record.url?scp=85094120212&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/science.abd4570
DO - https://doi.org/10.1126/science.abd4570
M3 - Article
C2 - 32972995
SN - 0036-8075
VL - 370
SP - 422-+
JO - Science
JF - Science
IS - 6515
M1 - eabd4570
ER -