X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

T. Asano, B. Boisson, F. Onodi, D. Matuozzo, M. Moncada-Velez, M.R.Luxman, M.Renkilaraj, P.Zhang, L.Meertens, A. Bolze, M. Materna, S. Korniotis, A. Gervais, E. Talouarn, B. Bigio, Y. Seeleuthner, K. Bilguvar, Y. Zhang, A. Neehus, M.Ogishi, S.J. Pelham, T.Le Voyer, J. Rosain, Q. Philippot, P.Soler-Palacín, R. Colobran, A. Martin-Nalda, J.G. Rivière, Y. Tandjaoui-Lambiotte, K. Chaïbi, M.Shahrooei, I.A. Darazam, N.A.Olyaei, D. Mansouri, N. Hatipoğlu, F.Palabiyik, T. Ozcelik, G. Novelli, A. Novelli, G. Casari, A. Aiuti, P. Carrera, S. Bondesan, F. Barzaghi, P. Rovere-Querini, C. Tresoldi, J.L.Franco, J. Rojas, L.F. Reyes, I.G. Bustos, A.A. Arias, G. Morelle, C. Kyheng, J. Troya, L. Planas-Serra, A. Schlüter, M. Gut, A. Pujol, L.M. Allende, C. Rodriguez-Gallego, C. Flores, O. Cabrera-Marante, D.E. Pleguezuelo, Diego, S. Keles, G. Aytekin, O. M. Akcan, Y.T. Bryceson, Peter Bergman, P .Brodin, D..Smole, C.I.E. Smith, A. Norlin, T.M. Campbell, L.E. Covill, L. Hammarstrom, Q. Pan-Hammarström, H. Abolhassani, S. Mane, N. Marr , M. Ata, F. Al Ali, T. Khan, A.N. Spaan, C.L. Dalgard, P. Bonfanti, A.Biondi, S Tubiana, C. Burdet, R. Nussbaum, A. Kahn-Kirby, AL. Snow, COVID Human Genetic Effort, COVID-STORM Clinicians, COVID Clinicians, Imagine COVID Group, French COVID Cohort Study Group, CoV-Contact Cohort, Amsterdam UMC Covid-19 Biobank, NIAID-USUHS COVID Study Group, J. Bustamante, A. Puel, S. Boisson-Dupuis, S. Zhang, V. Béziat, R.P. Lifton, P. Bastard, L.D. Notarangelo, L. Abel, H.C. Su, E. Jouanguy, A. Amara, V. Soumelis, A. Cobat, Q. Zhang, J.Casanova

August 20, 2021

Autosomal 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.

X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
June 22, 2022