Asano, TakakiBoisson, BertrandOnodi, FannyMatuozzo, DanielaMoncada Velez, MarcelaMaglorius Renkilaraj, Majistor Raj LuxmanZhang, PengMeertens, LaurentBolze, AlexandreMaterna, MarieKorniotis, SarantisKhan, TaushifSpaan, András N.Bonfanti, PaoloTubiana, SarahBurdet, CharlesNussbaum, Robert L.Kahn-Kirby, AmandaSnow, Andrew L.Bustamante, JacintaPuel, AnneLifton, Richard P.Boisson-Dupuis, StéphanieNotarangelo, Luigi D.Zhang, Shen-YingSu, Helen C.Béziat, VivienBastard, PaulAbel, LaurentJouanguy, EmmanuelleAmara, AliSoumelis, VassiliCobat, AurélieZhang, QianCasanova, Jean-LaurentCOVID Human Genetic EffortFrench COVID Cohort Study GroupCOVID-STORM CliniciansAmsterdam UMC Covid-19 BiobankCOVID CliniciansGervais, AdrianImagine COVID GroupCoV-Contact CohortNIAID-USUHS COVID Study GroupTalouarn, EstelleBigio, BenedettaSeeleuthner, YoannBilguvar, KayaZhang, YuNeehus, Anna-LenaOgishi, MasatoSoler Palacín, PerePelham, Simon J.Martin Nalda, AndreaLe Voyer, TomRosain, JérémiePhilippot, QuentinColobran, RogerRivière, Jacques G.Tandjaoui-Lambiotte, YacineChaïbi, KhalilShahrooei, MohammadDarazam, Ilad AlaviOlyaei, Nasrin AlipourMansouri, DavoodHatipoğlu, NevinCasari, GiorgioPalabiyik, FigenCarrera, PaolaOzcelik, TayfunNovelli, GiuseppeNovelli, AntonioAiuti, AlessandroBondesan, SimoneBarzaghi, FedericaRovere-Querini, PatriziaTresoldi, CristinaFranco, Jose LuisRojas, JulianReyes, Luis FelipeBustos, Ingrid G.Planas Serra, LauraArias, Andres AugustoGut, MartaMorelle, GuillaumeChristèle, KyhengTroya, JesúsSchlüter, AgathaPujol, Aurora, 1968-Allende, Luis M.Rodriguez Gallego, CarlosFlores, CarlosCabrera Marante, OscarPleguezuelo, Daniel E.Pérez de Diego, RebecaKeles, SevgiBrodin, PetterAytekin, GokhanSmith, C.I. EdvardAkcan, Ozge MetinBryceson, Yenan T.Bergman, PeterSmole, DanielNorlin, Anna-CarinCampbell, Tessa M.Covill, Laura E.Hammarström, LennartPan-Hammarström, QiangAbolhassani, HassanMane, ShrikantMarr, NicoDalgard, Clifton L.Ata, ManarBiondi, AndreaAl Ali, Fatima2021-10-042021-10-042021-08-192470-9468https://hdl.handle.net/2445/180375Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 × 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.22 p.application/pdfengcc by (c) Asano, Takaki et al, 2021http://creativecommons.org/licenses/by/3.0/es/COVID-19ProteïnesResposta immunitàriaCOVID-19ProteinsImmune responseinfo:eu-repo/semantics/article2021-10-01info:eu-repo/semantics/openAccess34413140