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

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dc.contributor.authorAsano, Takaki
dc.contributor.authorBoisson, Bertrand
dc.contributor.authorOnodi, Fanny
dc.contributor.authorMatuozzo, Daniela
dc.contributor.authorMoncada-Velez, Marcela
dc.contributor.authorRenkilaraj, Majistor Raj Luxman Maglorius
dc.contributor.authorZhang, Peng
dc.date.accessioned2024-02-23T14:26:09Z
dc.date.available2024-02-23T14:26:09Z
dc.date.issued2021
dc.departmentNEÜen_US
dc.description.abstractAutosomal 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 x 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 x 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.en_US
dc.description.sponsorshipHoward Hughes Medical Institute, Rockefeller University; St. Giles Foundation; NIH [R01AI088364]; National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program [UL1TR001866]; Fast Grant from Emergent Ventures; Mercatus Center at the George Mason University; GSP Coordinating Center - National Human Genome Research Institute (NHGRI) [UM1HG006504, U24HG008956]; Fisher Center for Alzheimer's Research Foundation; Meyer Foundation; JPB Foundation; French National Research Agency (ANR) [ANR-10-IAHU-01, ANR-10-LABX-62-IBEID]; French Foundation for Medical Research (FRM) [EQU201903007798]; FRM; ANR GENCOVID project; ANR GENVIR [ANR-20-CE93-003]; ANR AABIFNCOV [ANR-20-CO11-0001]; European Union [824110]; Square Foundation; SCOR Corporate Foundation for Science; Grandir-Fonds de solidarite pour l'enfance; Fondation du Souffle; Institut National de la Sante et de la Recherche Medicale (INSERM); REACTing-INSERM; University of Paris; INSERM; REACTing consortium; French Ministry of Health [(PHRC 20-0424]; French Ministry of Health; European Commission [RECOVER WP 6]; European Union's Horizon 2020 Research and Innovation Program (EasiGenomics grant) [824110 COVID-19/PID12342]; Instituto de Salud Carlos III [COV20_01333, COV20_01334]; Spanish Ministry of Science and Innovation (AEI/FEDER, UE) [RTC-2017-6471-1]; Fundacion DISA [OA18/017]; Cabildo Insular de Tenerife [CGIEU0000219140]; Cabildo Insular de Tenerife (Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19); ANR [ANR-10-IAHU-01, ANR-20-COVI-000, ANR-20-CO11-0004]; Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence [ANR-10-LABX-62-IBEID]; FRM [EQU202003010193]; University of Paris (Plan de Soutien Covid-19) [RACPL20FIR01-COVIDSOUL]; Division of Intramural Research, NIAID, NIH [1ZIAAI001265, ZIA AI001270]; Italian Ministry of Health [COVID-2020-12371617]; intramural COVID Host Genetics program; Cooperation Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX) [806-2018]; Colciencias [713-2016, 111574455633]; ANR DENDRISEPSIS [ANR-17-CE15-0003]; ANR APCOD [ANR-17-CE15-0003-01]; Mercatus Center; University of Paris PLAN D'URGENCE COVID19; Sidra Medicine [SDR400048]; Qatar National Research Fund [NPRP9-251-3-045]; Bettencourt Schueller Foundation; International PhD program of the Imagine Institute; Center for Medical Innovation (CIMED); Swedish Medical Research Council; Stockholm County Council (ALF-project); Yale Center for Mendelian Genomics; [A0375-2020-36663]; [ANRS-COV05]; Agence Nationale de la Recherche (ANR) [ANR-17-CE15-0003] Funding Source: Agence Nationale de la Recherche (ANR)en_US
dc.description.sponsorshipThe Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, Rockefeller University; the St. Giles Foundation; the NIH (R01AI088364), the National Center for Advancing Translational Sciences (NCATS); NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866); a Fast Grant from Emergent Ventures; Mercatus Center at the George Mason University; the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956); the Fisher Center for Alzheimer's Research Foundation; the Meyer Foundation; the JPB Foundation; the French National Research Agency (ANR) under the Investments for the Futureprogram (ANR-10-IAHU-01) and the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID); the French Foundation for Medical Research (FRM) (EQU201903007798); the FRM and ANR GENCOVID project, the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003), and ANR AABIFNCOV (ANR-20-CO11-0001) projects; the European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 824110 (EASI-genomics); the Square Foundation; Grandir-Fonds de solidarite pour l'enfance; the SCOR Corporate Foundation for Science; Fondation du Souffle; Institut National de la Sante et de la Recherche Medicale (INSERM); REACTing-INSERM; and the University of Paris. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). The Neurometabolic Diseases Laboratory received funding from the European Union's Horizon 2020 Research and Innovation Program (EasiGenomics grant no. 824110 COVID-19/PID12342). A.P., R.P.d.D., C.R.-G., and C.F. were funded by Instituto de Salud Carlos III (COV20_01333 and COV20_01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundacion DISA (OA18/017), and Cabildo Insular de Tenerife (CGIEU0000219140 and Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19). The laboratories of G.N. and A.N. were supported by a grant awarded to Regione Lazio (PROGETTI DI GRUPPI DI RICERCA 2020) no. A0375-2020-36663, GecoBiomark. A. Amara's laboratory was supported by ANR under the Investments for the Futureprogram (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the FRM (EQU202003010193), ANR (ANR-20-COVI-000 project IDISCOVR and ANR-20-CO11-0004 project FISHBP), and the University of Paris (Plan de Soutien Covid-19: RACPL20FIR01-COVIDSOUL). This work was supported, in part, by the Division of Intramural Research, NIAID, NIH (grants 1ZIAAI001265 to H.C.S. and ZIA AI001270 to L.D.N.). The G.C. laboratory was supported by the Italian Ministry of Health (grant COVID-2020-12371617) and the intramural COVID Host Genetics program. The J.L.F. laboratory was supported, in part, by the Cooperation Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX; 806-2018) and Colciencias contract 713-2016 (no. 111574455633). The V.S. laboratory was supported by ANR DENDRISEPSIS (ANR-17-CE15-0003) and ANR APCOD (ANR-17-CE15-0003-01), a Fast Grant from the Mercatus Center, FRM, University of Paris PLAN D'URGENCE COVID19. The N.M.; laboratory was supported by Sidra Medicine (SDR400048) and the Qatar National Research Fund (grant No. NPRP9-251-3-045). A.-L.N. was supported by the Bettencourt Schueller Foundation and the International PhD program of the Imagine Institute. P. Bergman and C.I.E.S received support from the Center for Medical Innovation (CIMED), the Swedish Medical Research Council and the Stockholm County Council (ALF-project). Part of this work was generated within the European Reference Network for rare primary immunodeficiency, autoinflammatory and autoimmune diseases (RITA).en_US
dc.identifier.doi10.1126/sciimmunol.abl4348
dc.identifier.issn2470-9468
dc.identifier.issue62en_US
dc.identifier.pmid34413140en_US
dc.identifier.scopus2-s2.0-85113561257en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1126/sciimmunol.abl4348
dc.identifier.urihttps://hdl.handle.net/20.500.12452/14071
dc.identifier.volume6en_US
dc.identifier.wosWOS:000695969700003en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAmer Assoc Advancement Scienceen_US
dc.relation.ispartofScience Immunologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[Keyword Not Available]en_US
dc.titleX-linked recessive TLR7 deficiency in ?1% of men under 60 years old with life-threatening COVID-19en_US
dc.typeArticleen_US

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