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

Qian Zhang Paul BastardZhiyong LiuJérémie Le Pen Marcela Moncada-VelezJie ChenMasato Ogishi Ira K D Sabli Stephanie Hodeib Cecilia KorolJérémie RosainKaya BilguvarJunqiang YeAlexandre Bolze Benedetta Bigio Jean-Laurent Casanova Andrés Augusto Arias Qinhua ZhouYu ZhangFanny OnodiSarantis KorniotisLéa KarpfQuentin PhilippotMarwa Chbihi Lucie Bonnet-Madin Karim Dorgham Nikaïa Smith William M Schneider Brandon S Razooky Hans-Heinrich Hoffmann Eleftherios MichailidisLeen MoensJi Eun Han Lazaro Lorenzo Lucy Bizien Philip Meade Anna-Lena Neehus Aileen Camille UgurbilAurélien CorneauGaspard Kerner Peng Zhang Franck RapaportYoann SeeleuthnerJérémy Manry Cecile MassonYohann SchmittAgatha Schlüter Tom Le Voyer Taushif KhanJuan LiJacques Fellay Lucie RousselMohammad ShahrooeiMohammed F AlosaimiDavood MansouriHaya Al-SaudFahd Al-Mulla Feras AlmourfiSaleh Zaid Al-MuhsenFahad Alsohime Saeed H Al Turki Rana Hasanato Diederik van de BeekAndrea BiondiLaura Rachele BettiniMariella D'Angio'Bonfanti PaoloLuisa ImbertiAlessandra SottiniSimone PagheraEugenia Quiros-RoldanCamillo RossiAndrew J Oler Miranda F Tompkins Camille AlbaIsabelle VandernootJean-Christophe GoffardGuillaume SmitsIsabelle MigeotteFilomeen HaerynckPere Soler-Palacin Andrea Martin-Nalda Roger ColobranPierre-Emmanuel MorangeSevgi KelesFatma ÇölkesenTayfun OzcelikKadriye Kart Yasar Sevtap Şenoğlu Semsi Nur Karabela Carlos Flores Giuseppe NovelliSami HraiechYacine Tandjaoui-LambiotteXavier DuvalCédric Laouénannull nullnull nullnull nullnull nullnull nullnull nullnull nullnull nullAndrew L Snow Clifford L DalgardJoshua D MilnerDonald C Vinh Trine Hyrup Mogensen Nico Marr András N Spaan Bertrand Boisson Stéphanie Boisson-Dupuis Jacinta Bustamante Anne Puel Michael J Ciancanelli Isabelle Meyts Tom ManiatisVassili SoumelisAli AmaraMichel C Nussenzweig Adolfo García-Sastre Florian Krammer Aurora Pujol Darragh DuffyRichard P LiftonShen-Ying ZhangGuy GorochovVivien Béziat Emmanuelle Jouanguy Sancho-Shimizu VanessaCharles M RiceLaurent Abel Luigi Daniele Notarangelo Aurélie Cobat Helen C Su Jean Laurent Casanova

Published in: Science (New York, N.Y.) (2020)

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.