X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
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Asano T, Boisson B, Onodi F, Matuozzo D, Moncada-Velez M, Maglorius Renkilaraj MRL, Zhang P, Meertens L, Bolze A, Materna M, Korniotis S, Gervais A, Talouarn E, Bigio B, Seeleuthner Y, Bilguvar K, Zhang Y, Neehus AL, Ogishi M, Pelham SJ, Le Voyer T, Rosain J, Philippot Q, Soler-Palacín P, Colobran R, Martin-Nalda A, Rivière JG, Tandjaoui-Lambiotte Y, Chaïbi K, Shahrooei M, Darazam IA, Olyaei NA, Mansouri D, Hatipoğlu 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 JL, Rojas J, Reyes LF, Bustos IG, Arias AA, Morelle G, Kyheng C, Troya J, Planas-Serra L, Schlüter A, Gut M, Pujol A, Allende LM, Rodriguez-Gallego C, Flores C, Cabrera-Marante O, Pleguezuelo DE, Pérez de Diego R, Keles S, Aytekin G, Metin Akcan O, Bryceson YT, Bergman P, Brodin P, Smole D, Smith CIE, Norlin AC, Campbell TM, Covill LE, Hammarström L, Pan-Hammarström Q, Abolhassani H, Mane S, Marr N, Ata M, Al Ali F, Khan T, Spaan AN, 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Linglart A, López-Collazo E, Lorenzo-Salazar JM, Louapre C, Lubetzki C, Lung KC, Luyt CE, Lye DC, Magnone C, Mansouri D, Marchioni E, Marioli C, Marjani M, Marques L, Pereira JM, Martín-Nalda A, Pueyo DM, Martinez-Picado J, Marzana I, Mata-Martínez C, Mathian A, Matos LR, Matthews GV, Mayaux J, McLaughlin-Garcia R, Meersseman P, Mège JL, Mekontso-Dessap A, Melki I, Meloni F, Meritet JF, Merlani P, Akcan ÖM, Meyts I, Mezidi M, Migeotte I, Millereux M, Million M, Mirault T, Mircher C, Mirsaeidi M, Mizoguchi Y, Modi BP, Mojoli F, Moncomble E, Melián AM, Martinez AM, Morandeira F, Morange PE, Mordacq C, Morelle G, Mouly SJ, Muñoz-Barrera A, Nafati C, Nagashima S, Nakagama Y, Neven B, Neves JF, Ng LF, Ng YY, Nielly H, Medina YN, Cuadros EN, Ocejo-Vinyals JG, Okamoto K, Oualha M, Ouedrani A, Özçelik T, Ozkaya-Parlakay A, Pagani M, Pan-Hammarström Q, Papadaki M, Parizot C, Parola P, Pascreau T, Paul S, Paz-Artal E, Pedraza S, González Pellecer NC, Pellegrini S, de Diego RP, Pérez-Fernández XL, Philippe A, Philippot Q, Picod A, de Chambrun MP, Piralla A, Planas-Serra L, Ploin D, Poissy J, Poncelet G, Poulakou G, Pouletty MS, Pourshahnazari P, Qiu-Chen JL, Quentric P, Rambaud T, Raoult D, Raoult V, Rebillat AS, Redin C, Resmini L, Ricart P, Richard JC, Rigo-Bonnin R, Rivet N, Rivière JG, Rocamora-Blanch G, Rodero MP, Rodrigo C, Rodriguez LA, Rodriguez-Gallego C, Rodriguez-Palmero A, Romero CS, Rothenbuhler A, Roux D, Rovina N, Rozenberg F, Ruch Y, Ruiz M, Ruiz del Prado MY, Ruiz-Rodriguez JC, Sabater-Riera J, Saks K, Salagianni M, Sanchez O, Sánchez-Montalvá A, Sánchez-Ramón S, Schidlowski L, Schluter A, Schmidt J, Schmidt M, Schuetz C, Schweitzer CE, Scolari F, Sediva A, Seijo L, Seminario AG, Sene D, Seng P, Senoglu S, Seppänen M, Llovich AS, Shahrooei M, Shcherbina A, Siguret V, Siouti E, Smadja DM, Smith N, Sobh A, Solanich X, Solé-Violán J, Soler C, Soler-Palacín P, Sözeri B, Stella GM, Stepanovskiy Y, Stoclin A, Taccone F, Tandjaoui-Lambiotte Y, Taupin JL, Tavernier SJ, Tello LV, Terrier B, Thiery G, Thorball C, Thorn K, Thumerelle C, Tipu I, Tolstrup M, Tomasoni G, Toubiana J, Alvarez JT, Triantafyllia V, Trouillet-Assant S, Troya J, Tsang OTY, Tserel L, Tso EYK, Tucci A, Tüter Öz ŞK, Ursini MV, Utsumi T, Uzunhan Y, Vabres P, Valencia-Ramos J, Van Den Rym AM, Vandernoot I, Velez-Santamaria V, Zuniga Veliz SP, Vidigal MC, Viel S, Vilain C, Vilaire-Meunier ME, Villar-García J, Vincent A, Vogt G, Voiriot G, Volokha A, Vuotto F, Wauters E, Wauters J, Wu AKL, Wu TC, Yahşi A, Yesilbas O, Yildiz M, Young BE, Yükselmiş U, Zatz M, Zecca M, Zuccaro V, Jens VP, Lambrecht BN, Eva VB, Cédric B, Levi H, Eric H, Bauters F, De Clercq J, Cathérine H, Hans S, Leslie N, Florkin B, Boulanger C, Vanderlinden D, Annereau JP, Briseño-Roa L, Gribouval O, Pelet A, Abel L, Andrejak C, Angoulvant F, Bachelet D, Bartoli M, Basmaci R, Behilill S, Beluze M, Benkerrou D, Bhavsar K, Bouadma L, Bouchez S, Bouscambert M, Cervantes-Gonzalez M, Chair A, Chirouze C, Coelho A, 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Sci Immunol 6 (62) eabl4348 [2021-08-10; online 2021-08-10]
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 1,202 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, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) 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 < 6.5x10-4 We also 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.
PubMed 34413140
DOI 10.1126/sciimmunol.abl4348
Crossref 10.1126/sciimmunol.abl4348
pii: 6/62/eabl4348