Academic Journal
X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
| العنوان: | X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19 |
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| المؤلفون: | Asano T., Boisson B., Onodi F., Matuozzo D., Moncada-Velez M., Renkilaraj M.R.L.M., Zhang P. |
| بيانات النشر: | American Association for the Advancement of Science |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | interferon, toll like receptor 7, TLR7 protein, human, adolescent, adult, aged, Article, asymptomatic coronavirus disease 2019, B lymphocyte, bone marrow cell, child, clinical article, cohort analysis, coronavirus disease 2019, critical illness, disease severity, gene frequency, gene mutation, genetic variability, hemizygosity, human cell, immunity, male, men's health, middle aged, penetrance, phenotype, plasmacytoid dendritic cell, school child |
| الوصف: | 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. Copyright © 2021 ; Horizon 2020 Framework Programme, H2020: 824110 |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 2470-9468 |
| Relation: | Science Immunology; Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı; https://doi.org/10.1126/sciimmunol.abl4348; https://hdl.handle.net/20.500.12831/9290; 62; 2-s2.0-85113561257 |
| DOI: | 10.1126/sciimmunol.abl4348 |
| الاتاحة: | https://doi.org/10.1126/sciimmunol.abl4348 https://hdl.handle.net/20.500.12831/9290 |
| Rights: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.561CDBF6 |
| قاعدة البيانات: | BASE |
| تدمد: | 24709468 |
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| DOI: | 10.1126/sciimmunol.abl4348 |