@article{Asano_T-2021_214283,
title = {X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19},
author = {Asano, T. and Boisson, B. and Onodi, F. and Matuozzo, D. and Moncada-Velez, M. and Maglorius Renkilaraj, M. and Zhang, P. and Meertens, L. and Bolze, A. and Materna, M. and Korniotis, S. and Gervais, A. and Talouarn, E. and Bigio, B. and Seeleuthner, Y. and Bilguvar, K. and Zhang, Y. and Neehus, A. and Ogishi, M. and Pelham, S. and Le Voyer, T. and Rosain, J. and Philippot, Q. and Soler-Palacín, P. and Colobran, R. and Martin-Nalda, A. and Rivière, J. and Tandjaoui-Lambiotte, Y. and Chaïbi, K. and Shahrooei, M. and Darazam, I. and Olyaei, N. and Mansouri, D. and Hatipoğlu, N. and Palabiyik, F. and Ozcelik, T. and Novelli, G. and Novelli, A. and Casari, G. and Aiuti, A. and Carrera, P. and Bondesan, S. and Barzaghi, F. and Rovere-Querini, P. and Tresoldi, C. and Franco, J. and Rojas, J. and Reyes, L. and Bustos, I. and Arias, A. and Morelle, G. and Kyheng, C. and Troya, J. and Planas-Serra, L. and Schlüter, A. and Gut, M. and Pujol, A. and Allende, L. and Rodriguez-Gallego, C. and Flores, C. and Cabrera-Marante, O. and Pleguezuelo, D. and Pérez de Diego, R. and Keles, S. and Aytekin, G. and Metin Akcan, O. and Bryceson, Y. and Bergman, P. and Brodin, P. and Smole, D. and Smith, C. and Norlin, A. and Campbell, T. and Covill, L. and Hammarström, L. and Pan-Hammarström, Q. and Abolhassani, H. and Mane, S. and Marr, N. and Ata, M. and Al Ali, F. and Khan, T. and Spaan, A. and Dalgard, C. and Bonfanti, P. and Biondi, A. and Tubiana, S. and Burdet, C. and Nussbaum, R. and Kahn-Kirby, A. and Snow, A. and Bustamante, J. and Puel, A. and Boisson-Dupuis, S. and Zhang, S. and Béziat, V. and Lifton, R. and Bastard, P. and Notarangelo, L. and Abel, L. and Su, H. and Jouanguy, E. and Amara, A. and Soumelis, V. and Cobat, A. and Zhang, Q. and Casanova, J. and Covid Human Genetic Effort and Covid Storm Clinicians and Covid Clinicians and Imagine Covid Group and French Covid Cohort Study and COV-Contact-Cohort and Amsterdam UMC COVID-19 Biobank and NIAID-USUHS Covid Study Group},
month = {aug},
year = {2021},
abstract = {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-linkedTLR7variants 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 suchTLR7variants (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 deleteriousTLR7variants in the male general population is &lt;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-typeTLR7. 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.},
volume = {6},
issue = {62},
journal = {Science Immunology},
publisher = {American Association for the Advancement of Science},
url = {https://doi.org/10.1126/sciimmunol.abl4348},
}
