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.

• Authors: Takaki Asano, Bertrand Boisson, Fanny Onodi, Daniela Matuozzo, Marcela Moncada-Velez, Majistor Raj Luxman Maglorius Renkilaraj, Peng Zhang, Laurent Meertens, Alexandre Bolze, Marie Materna, Sarantis Korniotis, Adrian Gervais, Estelle Talouarn, Benedetta Bigio, Yoann Seeleuthner, Kaya Bilguvar, Yu Zhang, Anna-Lena Neehus, Masato Ogishi, Simon J Pelham, Tom Le Voyer, Jérémie Rosain, Quentin Philippot, Pere Soler-Palacín, Roger Colobran, Andrea Martin-Nalda, Jacques G Rivière, Yacine Tandjaoui-Lambiotte, Khalil Chaïbi, Mohammad Shahrooei, Ilad Alavi Darazam, Nasrin Alipour Olyaei, Davood Mansouri, Nevin Hatipoğlu, Figen Palabiyik, Tayfun Ozcelik, Giuseppe Novelli, Antonio Novelli, Giorgio Casari, Alessandro Aiuti, Paola Carrera, Simone Bondesan, Federica Barzaghi, Patrizia Rovere-Querini, Cristina Tresoldi, Jose Luis Franco, Julian Rojas, Luis Felipe Reyes, Ingrid G Bustos, Andres Augusto Arias, Guillaume Morelle, Kyheng Christèle, Jesús Troya, Laura Planas-Serra, Agatha Schlüter, Marta Gut, Aurora Pujol, Luis M Allende, Carlos Rodriguez-Gallego, Carlos Flores, Oscar Cabrera-Marante, Daniel E Pleguezuelo, Rebeca Pérez de Diego, Sevgi Keles, Gokhan Aytekin, Ozge Metin Akcan, Yenan T Bryceson, Peter Bergman, Petter Brodin, Daniel Smole, C I Edvard Smith, Anna-Carin Norlin, Tessa M Campbell, Laura E Covill, Lennart Hammarström, Qiang Pan-Hammarström, Hassan Abolhassani, Shrikant Mane, Nico Marr, Manar Ata, Fatima Al Ali, Taushif Khan, András N Spaan, Clifton L Dalgard, Paolo Bonfanti, Andrea Biondi, Sarah Tubiana, Charles Burdet, Robert Nussbaum, Amanda Kahn-Kirby, Andrew L Snow, 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, Jacinta Bustamante, Anne Puel, Stéphanie Boisson-Dupuis, Shen-Ying Zhang, Vivien Béziat, Richard P Lifton, Paul Bastard, Luigi D Notarangelo, Laurent Abel, Helen C Su, Emmanuelle Jouanguy, Ali Amara, Vassili Soumelis, Aurélie Cobat, Qian Zhang, Jean-Laurent Casanova
• Journal: Science immunology (Sci Immunol) Vol. 6 Issue 62 (08 19 2021) ISSN: 2470-9468 [Electronic] United States
• PMID: 34413140 (Publication Type: Journal Article, Observational Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021, American Association for the Advancement of Science.

Chemical References

• TLR7 protein, human
• Toll-Like Receptor 7

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Alleles
• COVID-19 (complications)
• Child
• Child, Preschool
• Genetic Diseases, X-Linked (complications)
• Humans
• Immune System Diseases (complications)
• Infant
• Male
• Middle Aged
• Pedigree
• Penetrance
• Toll-Like Receptor 7 (deficiency, genetics)
• Young Adult