期刊
SCIENCE IMMUNOLOGY
卷 6, 期 62, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abl4348
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资金
- Howard 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)
A study revealed that rare X-linked TLR7 variants were found in 16 unrelated male individuals with critical COVID-19 pneumonia out of a cohort of 1202 male patients. No such variants were detected in 331 asymptomatic or mildly infected male individuals.
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 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.
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