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

被引：309

作者：

Asano, Takaki ^{[1
]}

Boisson, Bertrand ^{[1
,2
,3
]}

Onodi, Fanny ^{[4
]}

Matuozzo, Daniela ^{[2
,3
]}

Moncada-Velez, Marcela ^{[1
]}

Renkilaraj, Majistor Raj Luxman Maglorius ^{[2
,3
]}

Zhang, Peng ^{[1
]}

Meertens, Laurent ^{[4
]}

Bolze, Alexandre ^{[5
]}

Materna, Marie ^{[2
,3
]}

Korniotis, Sarantis ^{[6
]}

Gervais, Adrian ^{[2
,3
]}

Talouarn, Estelle ^{[2
,3
]}

Bigio, Benedetta ^{[1
]}

Seeleuthner, Yoann ^{[2
,3
]}

Bilguvar, Kaya ^{[7
,8
]}

Zhang, Yu ^{[9
,10
]}

Neehus, Anna-Lena ^{[2
,3
]}

Ogishi, Masato ^{[1
]}

Pelham, Simon J. ^{[1
]}

Le Voyer, Tom ^{[2
,3
]}

Rosain, Jeremie ^{[2
,3
]}

Philippot, Quentin ^{[2
,3
]}

Soler-Palacin, Pere ^{[11
,12
,13
]}

Colobran, Roger ^{[13
,14
,15
]}

Martin-Nalda, Andrea ^{[11
,12
,13
]}

Riviere, Jacques G. ^{[11
,12
,13
]}

Tandjaoui-Lambiotte, Yacine ^{[16
,17
]}

Chaibi, Khalil ^{[18
,19
]}

Shahrooei, Mohammad ^{[20
,21
]}

Darazam, Ilad Alavi ^{[22
,23
]}

Olyaei, Nasrin Alipour ^{[20
,21
]}

Mansouri, Davood ^{[24
,25
,26
]}

Palabiyik, Figen ^{[27
]}

Ozcelik, Tayfun ^{[28
]}

Novelli, Giuseppe ^{[29
,30
]}

Novelli, Antonio ^{[31
]}

Casari, Giorgio ^{[32
,33
]}

Aiuti, Alessandro ^{[32
,34
,35
,36
]}

Carrera, Paola ^{[33
]}

Bondesan, Simone ^{[33
]}

Barzaghi, Federica ^{[34
,35
,36
]}

Rovere-Querini, Patrizia ^{[32
,37
]}

Tresoldi, Cristina ^{[38
]}

Franco, Jose Luis ^{[39
]}

Rojas, Julian ^{[39
]}

Reyes, Luis Felipe ^{[40
]}

Bustos, Ingrid G. ^{[40
]}

Arias, Andres Augusto ^{[1
,39
,41
]}

Morelle, Guillaume ^{[42
]}

机构：

[1] Rockefeller Univ, Rockefeller Branch, St Giles Lab Human Genet Infect Dis, 1230 York Ave, New York, NY 10021 USA

[2] Necker Hosp Sick Children, INSERM U1163, Necker Branch, Lab Human Genet Infect Dis, Paris, France

[3] Univ Paris, Imagine Inst, Paris, France

[4] Univ Paris, Lab Genomes & Cell Biol Dis, CNRS UMR7212, INSERM U944,Res Inst St Louis,St Louis Hosp, Paris, France

[5] Helix, San Mateo, CA USA

[6] Univ Paris, INSERM U976, F-75006 Paris, France

[7] Yale Sch Med, Yale Ctr Genome Anal, New Haven, CT USA

[8] Yale Sch Med, Dept Genet, New Haven, CT USA

[9] NIAID, Lab Clin Immunol & Microbiol, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[10] NIAID, Clin Genom Program, NIH, Lab Clin Immunol & Microbiol,Div Intramural Res, 9000 Rockville Pike, Bethesda, MD 20892 USA

[11] Vall dHebron Univ Hosp HUVH, Vall dHebron Res Inst VHIR, Infect Immunocompromised Pediat Patients Res Grp, Vall dHebron Barcelona Hosp Campus, Barcelona, Catalonia, Spain

[12] Autonomous Univ Barcelona UAB, Vall dHebron Res Inst VHIR, Vall dHebron Univ Hosp HUVH, Pediat Infect Dis & Immunodeficiencies Unit, Vall dHebron Barcelona Hosp Campus, Barcelona, Catalonia, Spain

[13] Jeffrey Modell Diagnost & Res Ctr Primary Immunod, Barcelona, Catalonia, Spain

[14] Vall dHebron Univ Hosp HUVH, Vall dHebron Res Inst VHIR, Diagnost Immunol Grp, Vall dHebron Barcelona Hosp Campus, Barcelona, Catalonia, Spain

[15] Autonomous Univ Barcelona UAB, Vall dHebron Univ Hosp HUVH, Genet Dept, Immunol Div, Vall dHebron Barcelona Hosp Campus, Barcelona, Catalonia, Spain

[16] Avicenne Hosp, AP HP, Intens Care Unit, Bobigny, France

[17] INSERM U1272, Hypoxia & Lung, Bobigny, France

[18] Avicenne Hosp, AP HP, Anesthesiol & Crit Care Med Dept, Bobigny, France

[19] Sorbonne Univ, INSERM UMR S 1155, Common & Rare Kidney Dis, Paris, France

[20] Specialized Immunol Lab Dr Shahrooei, Sina Med Complex, Ahvaz, Iran

[21] Katholieke Univ Leuven, Dept Microbiol & Immunol, Clin & Diagnost Immunol, Leuven, Belgium

[22] Shahid Beheshti Univ Med Sci, Infect Dis & Trop Med Res Ctr, Tehran, Iran

[23] Shahid Beheshti Univ Med Sci, Loghman Hakim Hosp, Dept Infect Dis & Trop Med, Tehran, Iran

[24] Shahid Beheshti Univ Med Sci, Natl Res Inst TB & Lung Dis, Dept Clin Immunol & Infect Dis, Tehran, Iran

[25] Shahid Beheshti Univ Med Sci, Masih Daneshvari Hosp, Clin TB & Epidemiol Res Ctr, Natl Res Inst TB & Lung Dis NRITLD, Tehran, Iran

[26] Shahid Beheshti Univ Med Sci, Pediat Resp Dis Res Ctr, Natl Res Inst TB & Lung Dis, Tehran, Iran

[27] Univ Hlth Sci, Bakirkoy Dr Sadi Konuk Training & Res Hosp, Pediat Infect Dis Unit, Istanbul, Turkey

[28] Bilkent Univ, Dept Mol Biol & Genet, Bilkent, Turkey

[29] Univ Roma Tor Vergata, Dept Biomed & Prevent, Rome, Italy

[30] IRCCS, Neuromed Inst, Pozzilli, IS, Italy

[31] Bambino Gesu Children Hosp, Translat Cytogen Res Unit, Lab Med Genet, IRCCS, Rome, Italy

[32] Univ Vita Salute San Raffaele, Milan, Italy

[33] IRCCS San Raffaele Sci Inst, Clin Genom, Milan, Italy

[34] IRCCS San Raffaele Sci Inst, San Raffaele Telethon Inst Gene Therapy SR Tiget, Milan, Italy

[35] IRCCS San Raffaele Sci Inst, Pediat Immunohematol Unit, Milan, Italy

[36] IRCCS San Raffaele Sci Inst, BMT Program, Milan, Italy

[37] IRCCS San Raffaele Sci Inst, Div Immunol Transplantat & Infect Dis, Milan, Italy

[38] IRCCS Osped San Raffaele, Mol Hematol Unit, Milan, Italy

[39] Univ Antioquia UdeA, Sch Med, Dept Microbiol & Parasitol, Primary Immunodeficiencies Grp, Medellin, Colombia

[40] Univ La Sabana, Chia, Colombia

[41] Univ Antioquia UdeA, Sch Microbiol, Medellin, Colombia

[42] Univ Paris Saclay, Hop Bicetre, AP HP, Dept Gen Pediat, Le Kremlin Bicetre, France

[43] Infanta Leonor Univ Hosp, Dept Internal Med, Madrid, Spain

[44] Bellvitge Biomed Res Inst IDIBELL, Neurometab Dis Lab, Barcelona, Spain

[45] ISCIII, Ctr Biomed Res Rare Dis CIBERER, Madrid, Spain

[46] Barcelona Inst Sci & Technol BIST, Ctr Genom Regulat CRG, CNAG CRG, Baldiri Reixac 4, Barcelona 08028, Spain

[47] Catalan Inst Res & Adv Studies ICREA, Barcelona, Spain

[48] Univ Hosp 12 Octubre, Res Inst Hosp 12 Octubre 1 12, Immunol Dept, Madrid, Spain

[49] Univ Complutense Madrid, Madrid, Spain

[50] Univ Hosp Gran Canaria Dr Negrin, Dept Immunol, Canarian Hlth Syst, Las Palmas Gran Canaria, Spain

来源：

SCIENCE IMMUNOLOGY | 2021年 / 6卷 / 62期

基金：

英国医学研究理事会; 欧盟地平线“2020”;

关键词：

PLASMACYTOID DENDRITIC CELLS; PYOGENIC BACTERIAL-INFECTIONS; SINGLE-STRANDED RNA; TOLL-LIKE RECEPTORS; PROTECTIVE IMMUNITY; HOST-DEFENSE; RECOGNITION; REDUNDANT; SUBSETS; HUMANS;

D O I：

10.1126/sciimmunol.abl4348

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

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 x 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 x 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.

引用

页数：22

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