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 - Asano, Takaki
AU - Boisson, Bertrand
AU - Onodi, Fanny
AU - Matuozzo, Daniela
AU - Moncada-Velez, Marcela
AU - Maglorius Renkilaraj, Majistor Raj Luxman
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 - Amsterdam UMC Covid-19 Biobank
AU - van de Beek, Diederik
AU - Wiersinga, W. Joost
AU - de Bree, Godelieve J.
AU - Geerlings, Suzanne E.
AU - Goorhuis, Bram
AU - Grobusch, Martin P.
AU - Harris, Vanessa C.
AU - Hermans, Sabine M.
AU - Hovius, Joppe W. R.
AU - Nellen, Jeannine
AU - van der Poll, Tom
AU - Prins, Jan M.
AU - Stijnis, Cornelis S.
AU - van der Valk, Marc
AU - van Vugt, Michele
AU - Hollmann, Markus W.
AU - Preckel, Prof. dr. , Benedikt
AU - Veelo, Denise P.
AU - Mansouri, Davood
AU - Hatipoğlu, Nevin
AU - Palabiyik, Figen
AU - Ozcelik, Tayfun
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 - Bustos, Ingrid G
AU - Bugiani, M
N1 - Members of Amsterdam UMC Covid-19 Biobank: Michiel van Agtmael2, Anne Geke Algera1, Brent Appelman2, Frank van Baarle1, Diane Bax3, Martijn Beudel4, Harm Jan Bogaard5, Marije Bomers2, Peter Bonta5, Lieuwe Bos1, Michela Botta1, Justin de Brabander2, Godelieve de Bree2, Sanne de Bruin1, David T. P. Buis1, Marianna Bugiani5, Esther Bulle1, Osoul Chouchane2 Alex Cloherty3, Mirjam Dijkstra12, Dave A. Dongelmans1, Romein W. G. Dujardin1, Paul Elbers1, Lucas Fleuren1, Suzanne Geerlings2 Theo Geijtenbeek3, Armand Girbes1, Bram Goorhuis2, Martin P. Grobusch2, Florianne Hafkamp3, Laura Hagens1, Jorg Hamann7, Vanessa Harris2, Robert Hemke8, Sabine M. Hermans2 Leo Heunks1, Markus Hollmann6, Janneke Horn1, Joppe W. Hovius2, Menno D. de Jong9, Rutger Koning4, Endry H. T. Lim1, Niels van Mourik1, Jeaninne Nellen2, Esther J. Nossent5, Frederique Paulus1, Edgar Peters2, Dan A. I. Pina-Fuentes4, Tom van der Poll2, Bennedikt Preckel6, Jan M. Prins2, Jorinde Raasveld1, Tom Reijnders2, Maurits C. F. J. de Rotte12, Michiel Schinkel2, Marcus J. Schultz1, Femke A. P. Schrauwen12, Alex Schuurmans10, Jaap Schuurmans1, Kim Sigaloff1, Marleen A. Slim1,2, Patrick Smeele5, Marry Smit1, Cornelis S. Stijnis2, Willemke Stilma1, Charlotte Teunissen11, Patrick Thoral1, Anissa M. Tsonas1, Pieter R. Tuinman2, Marc van der Valk2, Denise Veelo6, Carolien Volleman1, Heder de Vries1, Lonneke A. Vught1,2, Michèle van Vugt2, Dorien Wouters12, A. H. (Koos) Zwinderman13, Matthijs C. Brouwer4, W. Joost Wiersinga2, Alexander P. J. Vlaar1, Diederik van de Beek (d.vandebeek@amsterdamumc.nl)4
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 - http://www.scopus.com/inward/record.url?scp=85113561257&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciimmunol.abl4348
DO - https://doi.org/10.1126/sciimmunol.abl4348
M3 - Article
C2 - 34413140
SN - 2470-9468
VL - 6
JO - Science immunology
JF - Science immunology
IS - 62
M1 - eabl4348
ER -