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

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, A. -L.; Ogishi, M.; Pelham, S. J.; 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, N. A.; Mansouri, D.; Hatipoglu, N.; Palabiyik, F.; Ozcelik, T.; Novelli, G.; Novelli, A.; Casari, G.; Aiuti, A.; Carrera, P.; Bondesan, S.; Barzaghi, F.; Rovere-Querini, P.; Tresoldi, C.; Franco, J. L.; Rojas, J.; Reyes, L. F.; Bustos, I. G.; Arias, A. A.; 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, D. E.; Diego, R. P. D.; 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, L. E.; Hammarstrom, L.; Pan-Hammarstrom, Q.; Abolhassani, H.; Mane, S.; Marr, N.; Ata, M.; Ali, F. A.; Khan, T.; Spaan, A. N.; Dalgard, C. L.; Bonfanti, P.; Biondi, A.; Tubiana, S.; Burdet, C.; Nussbaum, R.; Kahn-Kirby, A.; Snow, A. L.; Bustamante, J.; Puel, A.; Boisson-Dupuis, S.; Zhang, S. -Y.; Beziat, V.; Lifton, R. P.; Bastard, P.; Notarangelo, L. D.; Abel, L.; H. C., Su; Jouanguy, E.; Amara, A.; Soumelis, V.; Cobat, A.; Zhang, Q.; Casanova, J. -L.

doi:10.1126/sciimmunol.abl4348

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 / 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, A. -L.; Ogishi, M.; Pelham, S. J.; 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, N. A.; Mansouri, D.; Hatipoglu, N.; Palabiyik, F.; Ozcelik, T.; Novelli, G.; Novelli, A.; Casari, G.; Aiuti, A.; Carrera, P.; Bondesan, S.; Barzaghi, F.; Rovere-Querini, P.; Tresoldi, C.; Franco, J. L.; Rojas, J.; Reyes, L. F.; Bustos, I. G.; Arias, A. A.; 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, D. E.; Diego, R. P. D.; 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, L. E.; Hammarstrom, L.; Pan-Hammarstrom, Q.; Abolhassani, H.; Mane, S.; Marr, N.; Ata, M.; Ali, F. A.; Khan, T.; Spaan, A. N.; Dalgard, C. L.; Bonfanti, P.; Biondi, A.; Tubiana, S.; Burdet, C.; Nussbaum, R.; Kahn-Kirby, A.; Snow, A. L.; 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.. - In: SCIENCE IMMUNOLOGY. - ISSN 2470-9468. - 6:62(2021). [10.1126/sciimmunol.abl4348]