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Science Immunology

Publication date: 2021-08-01
Publisher: American Association for the Advancement of Science

Author:

Asano, Takaki
Boisson, Bertrand ; Onodi, Fanny ; Matuozzo, Daniela ; Moncada-Velez, Marcela ; Renkilaraj, Majistor Raj Luxman Maglorius ; 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, Jeremie ; Philippot, Quentin ; Soler-Palacin, Pere ; Colobran, Roger ; Martin-Nalda, Andrea ; Riviere, Jacques G ; Tandjaoui-Lambiotte, Yacine ; Chaibi, Khalil ; Shahrooei, Mohammad ; Darazam, Ilad Alavi ; Olyaei, Nasrin Alipour ; Mansouri, Davood ; 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 ; Kyheng, Christele ; Troya, Jesus ; Planas-Serra, Laura ; Schluter, Agatha ; Gut, Marta ; Pujol, Aurora ; Allende, Luis M ; Rodriguez-Gallego, Carlos ; Flores, Carlos ; Cabrera-Marante, Oscar ; Pleguezuelo, Daniel E ; de Diego, Rebeca Perez ; Keles, Sevgi ; Aytekin, Gokhan ; Akcan, Ozge Metin ; Bryceson, Yenan T ; Bergman, Peter ; Brodin, Petter ; Smole, Daniel ; Smith, CI Edvard ; Norlin, Anna-Carin ; Campbell, Tessa M ; Covill, Laura E ; Hammarstrom, Lennart ; Pan-Hammarstrom, Qiang ; Abolhassani, Hassan ; Mane, Shrikant ; Marr, Nico ; Ata, Manar ; Al Ali, Fatima ; Khan, Taushif ; Spaan, Andras N ; Dalgard, Clifton L ; Bonfanti, Paolo ; Biondi, Andrea ; Tubiana, Sarah ; Burdet, Charles ; Nussbaum, Robert ; Kahn-Kirby, Amanda ; Snow, Andrew L ; Bustamante, Jacinta ; Puel, Anne ; Boisson-Dupuis, Stephanie ; Zhang, Shen-Ying ; Beziat, Vivien ; Lifton, Richard P ; Bastard, Paul ; Notarangelo, Luigi D ; Abel, Laurent ; Su, Helen C ; Jouanguy, Emmanuelle ; Amara, Ali ; Soumelis, Vassili ; Cobat, Aurelie ; Zhang, Qian ; Casanova, Jean-Laurent

Keywords:

HOST-DEFENSE, HUMANS, Immunology, Life Sciences & Biomedicine, PLASMACYTOID DENDRITIC CELLS, PROTECTIVE IMMUNITY, PYOGENIC BACTERIAL-INFECTIONS, RECOGNITION, REDUNDANT, Science & Technology, SINGLE-STRANDED RNA, SUBSETS, TOLL-LIKE RECEPTORS, Adolescent, Adult, Aged, Aged, 80 and over, Alleles, COVID-19, Child, Child, Preschool, Genetic Diseases, X-Linked, Humans, Immune System Diseases, Infant, Male, Middle Aged, Pedigree, Penetrance, Toll-Like Receptor 7, Young Adult, 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, 3202 Clinical sciences, 3204 Immunology

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.