TY - JOUR
T1 - X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
AU - COVID Human Genetic Effort
AU - COVID-STORM Clinicians
AU - COVID Clinicians
AU - Imagine COVID Group
AU - French COVID Cohort Study Group
AU - CoV-Contact Cohort
AU - Amsterdam UMC Covid-19 Biobank
AU - NIAID-USUHS COVID Study Group
AU - Asano, Takaki
AU - Boisson, Bertrand
AU - Onodi, Fanny
AU - Matuozzo, Daniela
AU - Moncada-Velez, Marcela
AU - Renkilaraj, Majistor Raj Luxman Maglorius
AU - Zhang, Peng
AU - Meertens, Laurent
AU - Bolze, Alexandre
AU - Materna, Marie
AU - Korniotis, Sarantis
AU - Gervais, Adrian
AU - Talouarn, Estelle
AU - Bigio, Benedetta
AU - Seeleuthner, Yoann
AU - Bilguvar, Kaya
AU - Zhang, Yu
AU - Neehus, Anna Lena
AU - Ogishi, Masato
AU - Pelham, Simon J.
AU - Le Voyer, Tom
AU - Rosain, Jérémie
AU - Philippot, Quentin
AU - Soler-Palacín, Pere
AU - Colobran, Roger
AU - Martin-Nalda, Andrea
AU - Rivière, Jacques G.
AU - Tandjaoui-Lambiotte, Yacine
AU - Chaïbi, Khalil
AU - Shahrooei, Mohammad
AU - Darazam, Ilad Alavi
AU - Olyaei, Nasrin Alipour
AU - Mansouri, Davood
AU - Hatipoğlu, Nevin
AU - Palabiyik, Figen
AU - Novelli, Giuseppe
AU - Novelli, Antonio
AU - Casari, Giorgio
AU - Aiuti, Alessandro
AU - Carrera, Paola
AU - Bondesan, Simone
AU - Barzaghi, Federica
AU - Rovere-Querini, Patrizia
AU - Tresoldi, Cristina
AU - Franco, Jose Luis
AU - Rojas, Julian
AU - Reyes, Luis Felipe
AU - Halwani, Rabih
AU - Tayoun, Ahmad Abou
AU - Uddin, Mohammed J.
N1 - Publisher Copyright:
Copyright © 2021
PY - 2021/8/19
Y1 - 2021/8/19
N2 - 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 1202 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) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients 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 <6.5 × 10−4. We 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.
AB - 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 1202 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) or moderate (n = 1), severe (n = 1), or critical (n = 1) pneumonia. Two patients 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 <6.5 × 10−4. We 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.
UR - https://www.scopus.com/pages/publications/85113561257
U2 - 10.1126/sciimmunol.abl4348
DO - 10.1126/sciimmunol.abl4348
M3 - Article
C2 - 34413140
AN - SCOPUS:85113561257
SN - 2470-9468
VL - 6
JO - Science immunology
JF - Science immunology
IS - 62
M1 - eabl4348
ER -
SDG 3 Good Health and Well-being