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

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

Asano T,Boisson B,Onodi F,Matuozzo D,Moncada-Velez M,Maglorius Renkilaraj M,Zhang P,Meertens L,Bolze A,Materna M,Korniotis S,Gervais A,Talouarn E,Bigio B,Seeleuthner Y,Bilguvar K,Zhang Y,Neehus A,Ogishi M,Pelham S,Le Voyer T,Rosain J,Philippot Q,Soler-Palacín P,Colobran R,Martin-Nalda A,Rivière J,Tandjaoui-Lambiotte Y,Chaïbi K,Shahrooei M,Darazam I,Olyaei N,Mansouri D,Hatipoğlu N,Palabiyik F,Ozcelik T,Novelli G,Novelli A,Casari G,Aiuti A,Carrera P,Bondesan S,Barzaghi F,Rovere-Querini P,Tresoldi C,Franco J,Rojas J,Reyes L,Bustos I,Arias A,Morelle G,Christèle K,Troya J,Planas-Serra L,Schlüter A,Gut M,Pujol A,Allende L,Rodriguez-Gallego C,Flores C,Cabrera-Marante O,Pleguezuelo D,de Diego R,Keles S,Aytekin G,Akcan O,Bryceson Y,Bergman P,Brodin P,Smole D,Smith C,Norlin A,Campbell T,Covill L,Hammarström L,Pan-Hammarström Q,Abolhassani H,Mane S,Marr N,Ata M,Al Ali F,Khan T,Spaan A,Dalgard C,Bonfanti P,Biondi A,Tubiana S,Burdet C,Nussbaum R,Kahn-Kirby A,Snow A,Bustamante J,Puel A,Boisson-Dupuis S,Zhang S,Béziat V,Lifton R,Bastard P,Notarangelo L,Abel L,Su H,Jouanguy E,Amara A,Soumelis V,Cobat A,Zhang Q,Casanova J

Source :

2021 Aoû 20

Pmid / DOI:

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 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 variants ( = 3.5 × 10). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (=2, 5 and 38 years), or moderate (=1, 5 years), severe (=1, 27 years), or critical (=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 variants in the male general population is < 6.5x10 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 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, American Association for the Advancement of Science.

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