Zhang, QianBastard, PaulLiu, ZhiyongLe Pen, JeremieMoncada-Velez, MarcelaChen, JieOgishi, MasatoSabli, Ira K. D.Hodeib, StephanieKorol, CeciliaRosain, JeremieBilguvar, KayaYe, JunqiangBolze, AlexandreBigio, BenedettaYang, RuiArias, Andres AugustoZhou, QinhuaZhang, YuOnodi, FannyKorniotis, SarantisKarpf, LeaPhilippot, QuentinChbihi, MarwaBonnet-Madin, LucieDorgham, KarimSmith, NikaiaSchneider, William M.Razooky, Brandon S.Hoffmann, Hans-HeinrichMichailidis, EleftheriosMoens, LeenHan, Ji EunLorenzo, LazaroBizien, LucyMeade, PhilipNeehus, Anna-LenaUgurbil, Aileen CamilleCorneau, AurelienKerner, GaspardZhang, PengRapaport, FranckSeeleuthner, YoannManry, JeremyMasson, CecileSchmitt, YohannSchlueter, AgathaLe Voyer, TomKhan, TaushifLi, JuanFellay, JacquesRoussel, LucieShahrooei, MohammadAlosaimi, Mohammed F.Mansouri, DavoodAl-Saud, HayaAl-Mulla, FahdAlmourfi, FerasAl-Muhsen, Saleh ZaidAlsohime, FahadAl Turki, SaeedHasanato, Ranavan de Beek, DiederikBiondi, AndreaBettini, Laura RacheleD'Angio, MariellaBonfanti, PaoloImberti, LuisaSottini, AlessandraPaghera, SimoneQuiros-Roldan, EugeniaRossi, CamilloOler, Andrew J.Tompkins, Miranda F.Alba, CamilleVandernoot, IsabelleGoffard, Jean-ChristopheSmits, GuillaumeMigeotte, IsabelleHaerynck, FilomeenSoler-Palacin, PereMartin-Nalda, AndreaColobran, RogerMorange, Pierre-EmmanuelKeles, SevgiColkesen, FatmaOzcelik, TayfunYasar, Kadriye KartSenoglu, SevtapKarabela, Semsi NurRodriguez-Gallego, CarlosNovelli, GiuseppeHraiech, SamiTandjaoui-Lambiotte, YacineDuval, XavierLaouenan, CedricSnow, Andrew L.Dalgard, Clifton L.Milner, Joshua D.Vinh, Donald C.Mogensen, Trine H.Marr, NicoSpaan, Andras N.Boisson, BertrandBoisson-Dupuis, StephanieBustamante, JacintaPuel, AnneCiancanelli, Michael J.Meyts, IsabelleManiatis, TomSoumelis, VassiliAmara, AliNussenzweig, MichelGarcia-Sastre, AdolfoKrammer, FlorianPujol, AuroraDuffy, DarraghLifton, Richard P.Zhang, Shen-YingGorochov, GuyBeziat, VivienJouanguy, EmmanuelleSancho-Shimizu, VanessaRice, Charles M.Abel, LaurentNotarangelo, Luigi D.Cobat, AurelieSu, Helen C.Casanova, Jean-Laurent2020-11-052020-11-052020-11-052020-10-2310.1126/science.abd4570https://infoscience.epfl.ch/handle/20.500.14299/172998WOS:000581077200034Clinical 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.Multidisciplinary SciencesScience & Technology - Other Topicsherpes-simplex encephalitisnf-kappa-bdeficiencysusceptibilitytext::journal::journal article::research article