Human genetic and immunological determinants of critical COVID-19 pneumonia

Zhang, Q.; Bastard, P.; Karbuz, A.; Gervais, A.; Tayoun, A. A.; Aiuti, A.; Belot, A.; Bolze, A.; Gaudet, A.; Bondarenko, A.; Spaan, A. N.; Guennoun, A.; Arias, A. A.; Planas, A. M.; Sediva, A.; Shcherbina, A.; Neehus, A. -L.; Puel, A.; Froidure, A.; Novelli, A.; Parlakay, A. O.; Pujol, A.; Yahsi, A.; Gulhan, B.; Bigio, B.; Boisson, B.; Drolet, B. A.; Franco, C. A. A.; Flores, C.; Rodriguez-Gallego, C.; Prando, C.; Biggs, C. M.; Luyt, C. -E.; Dalgard, C. L.; O'Farrelly, C.; Matuozzo, D.; Dalmau, D.; Perlin, D. S.; Mansouri, D.; Van De Beek, D.; Vinh, D. C.; Dominguez-Garrido, E.; Hsieh, E. W. Y.; Erdeniz, E. H.; Jouanguy, E.; Sevketoglu, E.; Talouarn, E.; Quiros-Roldan, E.; Andreakos, E.; Husebye, E.; Alsohime, F.; Haerynck, F.; Casari, G.; Novelli, G.; Aytekin, G.; Morelle, G.; Alkan, G.; Bayhan, G. I.; Feldman, H. B.; H. C., Su; Von Bernuth, H.; Resnick, I.; Bustos, I.; Meyts, I.; Migeotte, I.; Tancevski, I.; Bustamantem, J.; Fellay, J.; El Baghdadi, J.; Martinez-Picado, J.; Casanova, J. -L.; Rosain, J.; Manry, J.; Chen, J.; Christodoulou, J.; Bohlen, J.; Franco, J. L.; Li, J.; Anaya, J. M.; Rojas, J.; Ye, J.; Uddin, K. M. F.; Yasar, K. K.; Kisand, K.; Okamoto, K.; Chaibi, K.; Mironska, K.; Marodi, L.; Abel, L.; Renia, L.; Lorenzo, L.; Hammarstrom, L.; L. F. P., Ng; Quintana-Murci, L.; Erazo, L. V.; Notarangelo, L. D.; Reyes, L. F.; Allende, L. M.; Imberti, L.; Renkilaraj, M. R. L. M.; Moncada-Velez, M.; Materna, M.; Anderson, M. S.; Gut, M.; Chbihi, M.; Ogishi, M.; Emiroglu, M.; Seppanen, M. R. J.; Uddin, M. J.; Shahrooei, M.; Alexander, N.; Hatipoglu, N.; Marr, N.; Akcay, N.; Boyarchuk, O.; Slaby, O.; Akcan, O. M.; Zhang, P.; Soler-Palacin, P.; Gregersen, P. K.; Brodin, P.; Garcon, P.; Morange, P. -E.; Pan-Hammarstrom, Q.; Zhou, Q.; Philippot, Q.; Halwani, R.; De Diego, R. P.; Levy, R.; Yang, R.; S. K. T., Oz; Muhsen, S. A.; Kanik-Yuksek, S.; Espinosa-Padilla, S.; Ramaswamy, S.; Okada, S.; Bozdemir, S. E.; Aytekin, S. E.; Karabela, S. N.; Keles, S.; Senoglu, S.; Zhang, S. -Y.; Duvlis, S.; Constantinescu, S. N.; Boisson-Dupuis, S.; Turvey, S. E.; Tangye, S. G.; Asano, T.; Ozcelik, T.; Le Voyer, T.; Maniatis, T.; Morio, T.; Mogensen, T. H.; Sancho-Shimizu, V.; Beziat, V.; Solanich, X.; Bryceson, Y.; Lau, Y. -L.; Itan, Y.; Cobat, A.; Casanova, J. -L.

doi:10.1038/s41586-022-04447-0

SARS-CoV-2 infection is benign in most individuals but, in ˜10% of cases, it triggers hypoxemic COVID-19 pneumonia, which becomes critical in ˜3% of cases. The ensuing risk of death (˜1%) doubles every five years from childhood onward and is ˜1.5 times greater in men than in women. What are the molecular and cellular determinants of critical COVID-19 pneumonia? Inborn errors of type I IFNs, including autosomal TLR3 and X-linked TLR7 deficiencies, are found in ˜1-5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing autoantibodies neutralizing IFN-α, –β, and/or –ω, which are more common in men than in women, are found in ˜15-20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can apparently be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defense against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation.