TY - JOUR
T1 - Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
AU - COVID-STORM Clinicians
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 - Li, Juan
AU - Stilma, Willemke
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 - 10.1126/science.abd4570
DO - 10.1126/science.abd4570
M3 - Article
C2 - 32972995
VL - 370
SP - 422-+
JO - Science (New York, N.Y.)
JF - Science (New York, N.Y.)
SN - 1095-9203
IS - 6515
M1 - eabd4570
ER -