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

Asano, Takaki and Boisson, Bertrand and Cvetkovski, Aleksandar and et, al. (2021) X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19. Science immunology., 6 (62). ISSN 2470-9468

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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 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.

Item Type: Article
Impact Factor Value: 19.1
Subjects: Medical and Health Sciences > Basic medicine
Medical and Health Sciences > Health sciences
Divisions: Faculty of Medical Science
Depositing User: Aleksandar Cvetkovski
Date Deposited: 28 May 2025 08:20
Last Modified: 02 Jun 2025 11:12
URI: https://eprints.ugd.edu.mk/id/eprint/35990

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