X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19

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.

• Autores: Arias Sierra, Andrés Augusto; Moncada Vélez, Marcela; Asano, Takaki; Boisson, Bertrand; Boisson Dupuis, Stéphanie; Bolze, Alexandre; Matuozzo, Daniela; Maglorius Renkilaraj, Majistor Raj Luxman; Zhang, Peng; Meertens, Laurent; Onodi, Fanny; Nussbaum, Robert; Kahn Kirby, Amanda; Snow, Andrew L.; Bustamante, Jacinta; Puel, Anne; Lifton, Richard P.; Bastard, Paul; Notarangelo, Luigi D; Su, Helen C; Jouanguy, Emmanuelle; Amara, Ali; Soumelis, Vassili; Cobat, Aurélie; Zhang, Qian; Casanova, Jean Laurent; 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; Alavi Darazam, Ilad; Alipour Olyaei, Nasrin; 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 Restrepo, José Luis; Rojas, Julian; Reyes, Luis Felipe; Bustos, Ingrid G.; Morelle, Guillaume; Guillaume, Morelle; Christèle, Kyheng; Troya, Jesús; Planas-Serra, Laura; Schlüter, Agatha; Pujol, Aurora; Allende, Luis M.; Rodríguez Gallego, Carlos; Flores, Carlos; Cabrera Marante, Oscar; Pleguezuelo, Daniel E.; Pérez de Diego, Rebeca; Keles, Sevgi; Aytekin, Gokhan; Metin Akcan, Ozge; Bryceson, Yenan T.; Bergman, Peter; Brodin, Petter; 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
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2021
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/40975
• Acceso en línea: https://hdl.handle.net/10495/40975
• Palabra clave: Alleles; Alelos; COVID-19; Genetic Diseases, X-Linked; Enfermedades Genéticas Ligadas al Cromosoma X; Immune System Diseases; Enfermedades del Sistema Inmune; Penetrance; Penetrancia; Toll-Like Receptor 7; Receptor Toll-Like 7; Middle Aged; Persona de Mediana Edad; Aged, 80 and over; Anciano de 80 o más Años; https://id.nlm.nih.gov/mesh/D000483; https://id.nlm.nih.gov/mesh/D000086382; https://id.nlm.nih.gov/mesh/D040181; https://id.nlm.nih.gov/mesh/D007154; https://id.nlm.nih.gov/mesh/D019683; https://id.nlm.nih.gov/mesh/D051199; https://id.nlm.nih.gov/mesh/D008875; https://id.nlm.nih.gov/mesh/D000369
• Rights: openAccess
• License: http://creativecommons.org/licenses/by/2.5/co/