X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.
Sci Immunol
; 6(62)2021 08 19.
Article
en En
| MEDLINE
| ID: mdl-34413140
ABSTRACT
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 1,202 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, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) 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 < 6.5x10-4 We also 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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Enfermedades Genéticas Ligadas al Cromosoma X
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Receptor Toll-Like 7
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COVID-19
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Enfermedades del Sistema Inmune
Tipo de estudio:
Observational_studies
Límite:
Adolescent
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Adult
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Aged
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Aged80
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Child
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Child, preschool
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Humans
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Infant
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Male
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Middle aged
Idioma:
En
Revista:
Sci Immunol
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos