X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
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Rodero, Mathieu P | Asano, Takaki | Boisson, Bertrand | Onodi, Fanny | Matuozzo, Daniela | Moncada-Velez, Marcela | Maglorius Renkilaraj, Majistor Raj Luxman | Zhang, Peng | Meertens, Laurent | Bolze, Alexandre | Materna, Marie | Korniotis, Sarantis | Gervais, Adrian | Talouarn, Estelle | Bigio, Benedetta | Seeleuthner, Yoann | Bilguvar, Kaya | Zhang, Yu | Neehus, Anna-Lena | Ogishi, Masato | Pelham, Simon | Le Voyer, Tom | Rosain, Jérémie | Philippot, Quentin | Soler-Palacín, Pere | Colobran, Roger | Martin-Nalda, Andrea | Rivière, Jacques | Tandjaoui-Lambiotte, Yacine | Chaïbi, Khalil | Shahrooei, Mohammad | Darazam, Ilad Alavi | Olyaei, Nasrin Alipour | Mansouri, Davood | Hatipoğlu, Nevin | Palabiyik, Figen | Ozcelik, Tayfun | Novelli, Giuseppe | Novelli, Antonio | Casari, Giorgio | Aiuti, Alessandro | Carrera, Paola | Bondesan, Simone | Barzaghi, Federica | Rovere-Querini, Patrizia | Tresoldi, Cristina | Franco, Jose Luis | Rojas, Julian | Reyes, Luis Felipe | Bustos, Ingrid | Arias, Andres Augusto | Morelle, Guillaume | Kyheng, Christèle | Troya, Jesús | Planas-Serra, Laura | Schlüter, Agatha | Gut, Marta | Pujol, Aurora | Allende, Luis | Rodriguez-Gallego, Carlos | Flores, Carlos | Cabrera-Marante, Oscar | Pleguezuelo, Daniel | Pérez de Diego, Rebeca | Keles, Sevgi | Aytekin, Gokhan | Metin Akcan, Ozge | Bryceson, Yenan | Bergman, Peter | Brodin, Petter | Smole, Daniel | Smith, C. | Norlin, Anna-Carin | Campbell, Tessa | Covill, Laura | Hammarström, Lennart | Pan-Hammarström, Qiang | Abolhassani, Hassan | Mane, Shrikant | Marr, Nico | Ata, Manar | Al Ali, Fatima | Khan, Taushif | Spaan, András | Dalgard, Clifton | Bonfanti, Paolo | Biondi, Andrea | Tubiana, Sarah | Burdet, Charles | Nussbaum, Robert | Kahn-Kirby, Amanda | Snow, Andrew | Bustamante, Jacinta | Puel, Anne | Boisson-Dupuis, Stéphanie | Zhang, Shen-Ying | Béziat, Vivien | Lifton, Richard | Bastard, Paul | Notarangelo, Luigi | Abel, Laurent | Su, Helen | Jouanguy, Emmanuelle | Amara, Ali | Soumelis, Vassili | Cobat, Aurélie | Zhang, Qian | Casanova, Jean-Laurent | Covid Cohort Study Group, French | Andréjak, Claire
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CCSD ; American Association for the Advancement of Science (AAAS) -
International audience.
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.
