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

Show full item record



Permalink

http://hdl.handle.net/10138/337727

Citation

French COVID Cohort Study Group , CoV-Contact Cohort , Amsterdam UMC Covid-19 Biobank , NIAID-USUHS COVID Study Group , COVID Human Genetic Effort , COVID-STORM Clinicians , COVID Clinicians , Imagine COVID Group , Asano , T , Boisson , B , Onodi , F & Seppänen , M 2021 , ' X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19 ' , Science immunology , vol. 6 , no. 62 , 4348 . https://doi.org/10.1126/sciimmunol.abl4348

Title: X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
Author: French COVID Cohort Study Group; CoV-Contact Cohort; Amsterdam UMC Covid-19 Biobank; NIAID-USUHS COVID Study Group; COVID Human Genetic Effort; COVID-STORM Clinicians; COVID Clinicians; Imagine COVID Group; Asano, Takaki; Boisson, Bertrand; Onodi, Fanny; Seppänen, Mikko
Contributor organization: Children's Hospital
HUS Children and Adolescents
Clinicum
Department of Medicine
Date: 2021-08-19
Language: eng
Number of pages: 22
Belongs to series: Science immunology
ISSN: 2470-9468
DOI: https://doi.org/10.1126/sciimmunol.abl4348
URI: http://hdl.handle.net/10138/337727
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.
Description: Publisher Copyright: Copyright © 2021
Subject: 3121 General medicine, internal medicine and other clinical medicine
PLASMACYTOID DENDRITIC CELLS
PYOGENIC BACTERIAL-INFECTIONS
SINGLE-STRANDED RNA
TOLL-LIKE RECEPTORS
PROTECTIVE IMMUNITY
HOST-DEFENSE
RECOGNITION
REDUNDANT
SUBSETS
HUMANS
PLASMACYTOID DENDRITIC CELLS
PYOGENIC BACTERIAL-INFECTIONS
SINGLE-STRANDED RNA
TOLL-LIKE RECEPTORS
PROTECTIVE IMMUNITY
HOST-DEFENSE
RECOGNITION
REDUNDANT
SUBSETS
HUMANS
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


Files in this item

Total number of downloads: Loading...

Files Size Format View
sciimmunol.abl4348.pdf 2.020Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record