- Published
- 24 October 2020
- Journal article
Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
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- Source
- Science
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Abstract
Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.
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Cite as
Zhang, Q., Bastard, P., Liu, Z., Le Pen, J., Moncada-Velez, M., Chen, J., Ogishi, M., Sabli, I., Hodeib, S., Korol, C., Rosain, J., Bilguvar, K., Ye, J., Bolze, A., Bigio, B., Yang, R., Arias, A., Zhou, Q., Zhang, Y., Onodi, F., Korniotis, S., Karpf, L., Philippot, Q., Chbihi, M., Bonnet-Madin, L., Dorgham, K., Smith, N., Schneider, W., Razooky, B., Hoffmann, H., Michailidis, E., Moens, L., Han, J., Lorenzo, L., Bizien, L., Meade, P., Neehus, A., Ugurbil, A., Corneau, A., Kerner, G., Zhang, P., Rapaport, F., Seeleuthner, Y., Manry, J., Masson, C., Schmitt, Y., Schlüter, A., Le Voyer, T., Khan, T., Li, J., Fellay, J., Roussel, L., Shahrooei, M., Alosaimi, M., Mansouri, D., Al-Saud, H., Al-Mulla, F., Almourfi, F., Al-Muhsen, S., Alsohime, F., Al Turki, S., Hasanato, R., van de Beek, D., Biondi, A., Bettini, L., D’Angio’, M., Bonfanti, P., Imberti, L., Sottini, A., Paghera, S., Quiros-Roldan, E., Rossi, C., Oler, A., Tompkins, M., Alba, C., Vandernoot, I., Goffard, J., Smits, G., Migeotte, I., Haerynck, F., Soler-Palacín, P., Martin-Nalda, A., Colobran, R., Morange, P., Keles, S., Çölkesen, F., Özçelik, T., Yasar, K., Senoglu, S., Karabela, Ş., Rodriguez-Gallego, C., Novelli, G., Hraiech, S., Tandjaoui-Lambiotte, Y., Duval, X., Laouénan, C., Snow, A., Dalgard, C., Milner, J., Vinh, D., Mogensen, T., Marr, N., Spaan, A., Boisson, B., Boisson-Dupuis, S., Bustamante, J., Puel, A., Ciancanelli, M., Meyts, I., Maniatis, T., Soumelis, V., Amara, A., Nussenzweig, M., García-Sastre, A., Krammer, F., Pujol, A., Duffy, D., Lifton, R., Zhang, S., Gorochov, G., Béziat, V., Jouanguy, E., Sancho-Shimizu, V., Rice, C., Abel, L., Notarangelo, L., Cobat, A., Su, H. & Casanova, J. 2020, 'Inborn errors of type I IFN immunity in patients with life-threatening COVID-19', Science, 370(6515), article no: eabd4570. https://doi.org/10.1126/science.abd4570