Publications
X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
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 J;
Le Voyer, Tom;
Rosain, Jérémie;
Philippot, Quentin;
Soler-Palacín, Pere;
Colobran, Roger;
Martin-Nalda, Andrea;
Rivière, Jacques G;
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 G;
Arias, Andres Augusto;
Morelle, Guillaume;
Christèle, Kyheng;
Troya, Jesús;
Planas-Serra, Laura;
Schlüter, Agatha;
Gut, Marta;
Pujol, Aurora;
Allende, Luis M;
Rodriguez-Gallego, Carlos;
Flores, Carlos;
Cabrera-Marante, Oscar;
Pleguezuelo, Daniel E;
de Diego, Rebeca Pérez;
Keles, Sevgi;
Aytekin, Gokhan;
Akcan, Ozge Metin;
Bryceson, Yenan T;
Bergman, Peter;
Brodin, Petter;
Smole, Daniel;
Smith, C I Edvard;
Norlin, Anna-Carin;
Campbell, Tessa M;
Covill, Laura E;
Hammarström, Lennart;
Pan-Hammarström, Qiang;
Abolhassani, Hassan;
Mane, Shrikant;
Marr, Nico;
Ata, Manar;
Al Ali, Fatima;
Khan, Taushif;
Spaan, András N;
Dalgard, Clifton L;
Bonfanti, Paolo;
Biondi, Andrea;
Tubiana, Sarah;
Burdet, Charles;
Nussbaum, Robert;
Kahn-Kirby, Amanda;
Snow, Andrew L;
COVID Human Genetic Effort, ;
COVID-STORM Clinicians, ;
COVID Clinicians, ;
Imagine COVID Group, ;
French COVID Cohort Study Group, ;
CoV-Contact Cohort, ;
Amsterdam UMC Covid-, ;
Biobank, ;
NIAID-USUHS COVID Study Group, ;
Bustamante, Jacinta;
Puel, Anne;
Boisson-Dupuis, Stéphanie;
Zhang, Shen-Ying;
Béziat, Vivien;
Lifton, Richard P;
Bastard, Paul;
Notarangelo, Luigi D;
Abel, Laurent;
Su, Helen C;
Jouanguy, Emmanuelle;
Amara, Ali;
Soumelis, Vassili;
Cobat, Aurélie;
Zhang, Qian;
Casanova, Jean-Laurent
Abstract
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.
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