X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19
Mathieu P Rodero
(1)
,
Takaki Asano
,
Bertrand Boisson
(2)
,
Fanny Onodi
,
Daniela Matuozzo
,
Marcela Moncada-Velez
,
Majistor Raj Luxman Maglorius Renkilaraj
(2)
,
Peng Zhang
(3)
,
Laurent Meertens
(4)
,
Alexandre Bolze
(5)
,
Marie Materna
(6)
,
Sarantis Korniotis
,
Adrian Gervais
,
Estelle Talouarn
,
Benedetta Bigio
,
Yoann Seeleuthner
,
Kaya Bilguvar
,
Yu Zhang
,
Anna-Lena Neehus
,
Masato Ogishi
,
Simon Pelham
,
Tom Le Voyer
,
Jérémie Rosain
,
Quentin Philippot
,
Pere Soler-Palacín
,
Roger Colobran
,
Andrea Martin-Nalda
,
Jacques Rivière
,
Yacine Tandjaoui-Lambiotte
,
Khalil Chaïbi
,
Mohammad Shahrooei
,
Ilad Alavi Darazam
,
Nasrin Alipour Olyaei
,
Davood Mansouri
,
Nevin Hatipoğlu
,
Figen Palabiyik
,
Tayfun Ozcelik
,
Giuseppe Novelli
,
Antonio Novelli
,
Giorgio Casari
,
Alessandro Aiuti
,
Paola Carrera
,
Simone Bondesan
,
Federica Barzaghi
,
Patrizia Rovere-Querini
,
Cristina Tresoldi
,
Jose Luis Franco
,
Julian Rojas
,
Luis Felipe Reyes
,
Ingrid Bustos
,
Andres Augusto Arias
,
Guillaume Morelle
,
Christèle Kyheng
,
Jesús Troya
,
Laura Planas-Serra
,
Agatha Schlüter
,
Marta Gut
,
Aurora Pujol
,
Luis Allende
,
Carlos Rodriguez-Gallego
,
Carlos Flores
,
Oscar Cabrera-Marante
,
Daniel Pleguezuelo
,
Rebeca Pérez de Diego
,
Sevgi Keles
,
Gokhan Aytekin
,
Ozge Metin Akcan
,
Yenan Bryceson
,
Peter Bergman
,
Petter Brodin
,
Daniel Smole
,
C. Smith
,
Anna-Carin Norlin
,
Tessa Campbell
,
Laura Covill
,
Lennart Hammarström
,
Qiang Pan-Hammarström
,
Hassan Abolhassani
,
Shrikant Mane
,
Nico Marr
,
Manar Ata
,
Fatima Al Ali
,
Taushif Khan
,
András Spaan
,
Clifton Dalgard
,
Paolo Bonfanti
,
Andrea Biondi
,
Sarah Tubiana
,
Charles Burdet
,
Robert Nussbaum
,
Amanda Kahn-Kirby
,
Andrew Snow
,
Jacinta Bustamante
,
Anne Puel
,
Stéphanie Boisson-Dupuis
,
Shen-Ying Zhang
,
Vivien Béziat
,
Richard Lifton
,
Paul Bastard
,
Luigi Notarangelo
,
Laurent Abel
,
Helen Su
,
Emmanuelle Jouanguy
,
Ali Amara
,
Vassili Soumelis
,
Aurélie Cobat
,
Qian Zhang
,
Jean-Laurent Casanova
,
French Covid Cohort Study Group
(7, 8)
,
Claire Andréjak
(9, 10, 11)
1
LCBPT - UMR 8601 -
Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
2 Necker Branch - INSERM U1163 - Laboratory of Human Genetics of Infectious Diseases
3 Rockefeller University [New York]
4 GenCellDi (U944 / UMR7212) - Génomes, biologie cellulaire et thérapeutiques
5 Helix [San Mateo, CA]
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 IP - Institut Pasteur [Paris]
8 GMV-ARN (UMR_3569 / U-Pasteur_2) - Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses
9 AGIR - Agents infectieux, résistance et chimiothérapie - UR UPJV 4294
10 CHU Amiens-Picardie
11 French COVID cohort study group
2 Necker Branch - INSERM U1163 - Laboratory of Human Genetics of Infectious Diseases
3 Rockefeller University [New York]
4 GenCellDi (U944 / UMR7212) - Génomes, biologie cellulaire et thérapeutiques
5 Helix [San Mateo, CA]
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 IP - Institut Pasteur [Paris]
8 GMV-ARN (UMR_3569 / U-Pasteur_2) - Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses
9 AGIR - Agents infectieux, résistance et chimiothérapie - UR UPJV 4294
10 CHU Amiens-Picardie
11 French COVID cohort study group
Mathieu P Rodero
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Takaki Asano
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Bertrand Boisson
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Majistor Raj Luxman Maglorius Renkilaraj
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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.
Domains
Life Sciences [q-bio]
Origin : Files produced by the author(s)