Asano, T.Boisson, B.Onodi, F.Matuozzo, D.Moncada-Velez, M.Renkilaraj, M. R. L. M.Zhang, P.Meertens, L.Bolze, A.Materna, M.Korniotis, S.Gervais, A.Talouarn, E.Bigio, B.Seeleuthner, Y.Bilguvar, K.Zhang, Y.Neehus, AL.Ogishi, M.Pelham, SJ.Le Voyer, T.Rosain, J.Philippot, Q.Soler-Palacin, P.Colobran, R.Martin-Nalda, A.Riviere, J. G.Tandjaoui-Lambiotte, Y.Chaibi, K.Shahrooei, M.Darazam, I. A.Olyaei, NA.Mansouri, D.Palabiyik, F.Özçelik, TayfunNovelli, G.Novelli, A.Casari, G.Aiuti, A.Carrera, P.Bondesan, S.Barzaghi, F.Rovere-Querini, P.Tresoldi, C.Franco, J. L.Rojas, J.Reyes, LF.Bustos, IG.Arias, AA.Morelle, G.Kyheng, C.Troya, J.Planas-Serra, L.Schluter, A.Gut, M.Pujol, A.Allende, L. M.Rodriguez-Gallego, C.Flores, C.Cabrera-Marante, O.Pleguezuelo, DE.de Diego, R. P.Keles, S.Aytekin, G.Akcan, O. M.Bryceson, Y. T.Bergman, P.Brodin, P.Smole, D.Smith, C. I. E.Norlin, A. C.Campbell, T. M.Covill, LE.Hammarstrom, L.Pan-Hammarstrom, Q.Abolhassani, H.Mane, S.Marr, N.Ata, M.Al Ali, F.Khan, T.Spaan, A. N.Dalgard, C. L.Bonfanti, P.Biondi, A.Tubiana, S.Burdet, C.Nussbaum, R.Kahn-Kirby, A.Snow, AL.Bustamante, J.Puel, A.Boisson-Dupuis, S.Zhang, S. Y.Beziat, V.Lifton, R. P.Bastard, P.Notarangelo, L. D.Abel, L.Su, H. C.Jouanguy, E.Amara, A.Soumelis, V.Cobat, A.Zhang, Q.Casanova, J. L.2022-01-272022-01-272021-08-20http://hdl.handle.net/11693/76832Autosomal 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 1202 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) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients 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 <6.5 × 10−4. We 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.EnglishArticle10.1126/sciimmunol.abl43482470-9468