Inborn errors of type I IFN immunity in patients with life-threatening COVID-19,Science

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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
Science ( IF 44.7 ) Pub Date : 2020-09-24 , DOI: 10.1126/science.abd4570
Qian Zhang ₁ , Paul Bastard _{2,

3} , Zhiyong Liu ₁ , Jérémie Le Pen ₄ , Marcela Moncada-Velez ₁ , Jie Chen ₁ , Masato Ogishi ₁ , Ira K D Sabli ₅ , Stephanie Hodeib ₅ , Cecilia Korol ₂ , Jérémie Rosain _{2,

3} , Kaya Bilguvar ₆ , Junqiang Ye ₇ , Alexandre Bolze ₈ , Benedetta Bigio ₁ , Rui Yang ₁ , Andrés Augusto Arias _{1,

9,

10} , Qinhua Zhou ₁ , Yu Zhang _{11,

12} , Fanny Onodi ₁₃ , Sarantis Korniotis ₁₃ , Léa Karpf ₁₃ , Quentin Philippot _{2,

3} , Marwa Chbihi _{2,

3} , Lucie Bonnet-Madin ₁₄ , Karim Dorgham ₁₅ , Nikaïa Smith ₁₆ , William M Schneider ₄ , Brandon S Razooky ₄ , Hans-Heinrich Hoffmann ₄ , Eleftherios Michailidis ₄ , Leen Moens ₁₇ , Ji Eun Han ₁ , Lazaro Lorenzo _{2,

3} , Lucy Bizien _{2,

3} , Philip Meade ₁₈ , Anna-Lena Neehus _{2,

3} , Aileen Camille Ugurbil ₁ , Aurélien Corneau ₁₉ , Gaspard Kerner _{2,

3} , Peng Zhang ₁ , Franck Rapaport ₁ , Yoann Seeleuthner _{2,

3} , Jeremy Manry _{2,

3} , Cecile Masson ₂₀ , Yohann Schmitt ₂₀ , Agatha Schlüter ₂₁ , Tom Le Voyer _{2,

3} , Taushif Khan ₂₂ , Juan Li ₁ , Jacques Fellay _{23,

24,

25} , Lucie Roussel ₂₆ , Mohammad Shahrooei _{27,

28} , Mohammed F Alosaimi ₂₉ , Davood Mansouri _{30,

31,

32} , Haya Al-Saud ₃₃ , Fahd Al-Mulla ₃₄ , Feras Almourfi ₃₃ , Saleh Zaid Al-Muhsen ₃₅ , Fahad Alsohime ₂₉ , Saeed Al Turki _{36,

37} , Rana Hasanato ₂₉ , Diederik van de Beek ₃₈ , Andrea Biondi ₃₉ , Laura Rachele Bettini ₃₉ , Mariella D'Angio' ₃₉ , Paolo Bonfanti ₄₀ , Luisa Imberti ₄₁ , Alessandra Sottini ₄₁ , Simone Paghera ₄₁ , Eugenia Quiros-Roldan ₄₂ , Camillo Rossi ₄₃ , Andrew J Oler ₄₄ , Miranda F Tompkins ₄₅ , Camille Alba ₄₅ , Isabelle Vandernoot ₄₆ , Jean-Christophe Goffard ₄₇ , Guillaume Smits ₄₆ , Isabelle Migeotte ₄₈ , Filomeen Haerynck ₄₉ , Pere Soler-Palacin ₅₀ , Andrea Martin-Nalda ₅₀ , Roger Colobran ₅₁ , Pierre-Emmanuel Morange ₅₂ , Sevgi Keles ₅₃ , Fatma Çölkesen ₅₄ , Tayfun Ozcelik ₅₅ , Kadriye Kart Yasar ₅₆ , Sevtap Senoglu ₅₆ , Şemsi Nur Karabela ₅₆ , Carlos Rodríguez-Gallego _{57,

58} , Giuseppe Novelli ₅₉ , Sami Hraiech ₆₀ , Yacine Tandjaoui-Lambiotte _{61,

62} , Xavier Duval _{63,

64} , Cédric Laouénan _{63,

64,

65} , , , , , , , , , Andrew L Snow ₆₆ , Clifton L Dalgard _{45,

67} , Joshua D Milner ₆₈ , Donald C Vinh ₂₆ , Trine H Mogensen _{69,

70} , Nico Marr _{22,

71} , András N Spaan _{1,

72} , Bertrand Boisson _{1,

2,

3} , Stéphanie Boisson-Dupuis _{1,

2,

3} , Jacinta Bustamante _{1,

2,

3,

73} , Anne Puel _{1,

2,

3} , Michael J Ciancanelli _{1,

74} , Isabelle Meyts _{17,

75} , Tom Maniatis _{7,

76} , Vassili Soumelis _{13,

77} , Ali Amara ₁₄ , Michel Nussenzweig _{78,

79} , Adolfo García-Sastre _{18,

80,

81,

82} , Florian Krammer ₁₈ , Aurora Pujol ₂₁ , Darragh Duffy ₁₆ , Richard P Lifton _{83,

84,

85} , Shen-Ying Zhang _{1,

2,

3} , Guy Gorochov ₁₅ , Vivien Béziat _{1,

2,

3} , Emmanuelle Jouanguy _{1,

2,

3} , Vanessa Sancho-Shimizu ₅ , Charles M Rice ₄ , Laurent Abel _{1,

2,

3} , Luigi D Notarangelo _{11,

12} , Aurélie Cobat _{1,

2,

3} , Helen C Su _{11,

12} , Jean-Laurent Casanova _{1,

2,

3,

79,

86}

Affiliation

St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
University of Paris, Imagine Institute, Paris, France.
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
Department of Paediatric Infectious Diseases & Virology, Imperial College London, London, UK.
Yale Center for Genome Analysis and Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
Zukerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.
Helix, San Mateo, CA, USA.
Primary Immunodeficiencies Group, University of Antioquia UdeA, Medellin, Colombia.
School of Microbiology, University of Antioquia UdeA, Medellin, Colombia.
Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
NIAID Clinical Genomics Program, NIH, Bethesda, MD, USA.
Université de Paris, Institut de Recherche Saint-Louis, INSERM U976, Hôpital Saint-Louis, Paris, France.
Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR 7212, Université de Paris, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France.
Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (CIMI PARIS), Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Pitié-Salpêtrière, Paris, France.
Translational Immunology Lab, Institut Pasteur, Paris, France.
Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, CIBERER U759, and Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar.
School of Life sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
Swiss Institue of Bioinformatics, Lausanne, Switzerland.
Infectious Disease Susceptibility Program, Research Institute, McGill University Health Centre, Montréal, Québec, Canada.
Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium.
Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
The Clinical Tuberculosis and Epidemiology Research Center, National Research Institute of, Tuberculosis and Lung Diseases (NRITLD), Masih Daneshvari Hospital, Shahid Beheshti, University of Medical Sciences, Tehran, Iran.
Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti, Iran.
National Center of Genomics Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
Dasman Diabetes Institute, Department of Genetics and Bioinformatics, Kuwait.
Immunology Research Laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
Translational Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Misery of National Guard Health Affairs, Riyadh, Saudi Arabia.
Cancer & Blood Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
Amsterdam UMC, Department of Neurology, Amsterdam Neuroscience, Amsterdam, Netherlands.
Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy.
Department of Infectious Diseases, San Gerardo Hospital-University of Milano-Bicocca, Monza, Italy.
CREA Laboratory, Diagnostic Laboratory, ASST Spedali Civili di Brescia, Brescia, Italy.
Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali di Brescia, Brescia, Italy.
Chief Medical Officer, ASST Spedali Civili di Brescia, Brescia, Italy.
Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA.
PRIMER, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
Department of Internal Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
Fonds de la Recherche Scientifique (FNRS) and Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
Department of Paediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency Ghent (CPIG), PID Research Lab, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium.
Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, Universitat Autònoma de Barcelona (UAB), Barcelona, Catalonia, Spain.
Immunology Division, Genetics Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, UAB, Barcelona, Catalonia, Spain.
Aix Marseille Univ, INSERM, INRAE, C2VN, CHU Timone, Marseille, France.
Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey.
Department of Infectious Diseases and Clinical Microbiology, Konya Training and Research Hospital, Konya, Turkey.
Department of Molecular Biology and Genetics, Bilkent University, Bilkent-Ankara, Turkey.
Departments of Infectious Diseases and Clinical Microbiology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
Department of Immunology, Hospital Universitario de G.C. Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain.
University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Rome, Italy.
Intensive Care Unit, AP-HM, Marseille, France.
Avicenne Hospital Intensive Care Unit, APHP, Bobigny, INSERM U1272 Hypoxia & Lung, Paris, France.
PH Réanimation CHU Avicenne, Bobigny, INSERM U1272 Hypoxie & Poumon, Paris, France.
Université de Paris, IAME UMR-S 1137, INSERM, Paris, France.
Inserm CIC 1425, Paris, France.
AP-HP, Département Epidémiologie Biostatistiques et Recherche Clinique, Hôpital Bichat, Paris, France.
Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Division of Pediatric Allergy, Immunology and Rheumatology, Columbia University, New York, USA.
Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark.
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
Department of Medical Microbiology, Utrecht UMC, Utrecht, Netherlands.
Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.
Turnstone Biologics, New York, NY, USA.
Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
New York Genome Center, New York, NY, USA.
AP-HP, Hôpital Saint-Louis, Laboratoire d'Immunologie, Paris, France.
Laboratory of Molecular Immunology, Rockefeller University, New York, NY, USA.
Howard Hughes Medical Institute, New York, NY, USA.
Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Laboratory of Genetics and Genomics, The Rockefeller University, New York, NY, USA.
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA.
Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.

The genetics underlying severe COVID-19 The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science, this issue p. eabd4570, p. eabd4585; see also p. 404 A large immunological and genomics study of COVID-19 patients reveals excess mutations in the type I IFN pathway. INTRODUCTION Clinical outcomes of human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection range from silent infection to lethal coronavirus disease 2019 (COVID-19). Epidemiological studies have identified three risk factors for severe disease: being male, being elderly, and having other medical conditions. However, interindividual clinical variability remains huge in each demographic category. Discovering the root cause and detailed molecular, cellular, and tissue- and body-level mechanisms underlying life-threatening COVID-19 is of the utmost biological and medical importance. RATIONALE We established the COVID Human Genetic Effort (www.covidhge.com) to test the general hypothesis that life-threatening COVID-19 in some or most patients may be caused by monogenic inborn errors of immunity to SARS-CoV-2 with incomplete or complete penetrance. We sequenced the exome or genome of 659 patients of various ancestries with life-threatening COVID-19 pneumonia and 534 subjects with asymptomatic or benign infection. We tested the specific hypothesis that inborn errors of Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity that underlie life-threatening influenza pneumonia also underlie life-threatening COVID-19 pneumonia. We considered three loci identified as mutated in patients with life-threatening influenza: TLR3, IRF7, and IRF9. We also considered 10 loci mutated in patients with other viral illnesses but directly connected to the three core genes conferring influenza susceptibility: TICAM1/TRIF, UNC93B1, TRAF3, TBK1, IRF3, and NEMO/IKBKG from the TLR3-dependent type I IFN induction pathway, and IFNAR1, IFNAR2, STAT1, and STAT2 from the IRF7- and IRF9-dependent type I IFN amplification pathway. Finally, we considered various modes of inheritance at these 13 loci. RESULTS We found an enrichment in variants predicted to be loss-of-function (pLOF), with a minor allele frequency <0.001, at the 13 candidate loci in the 659 patients with life-threatening COVID-19 pneumonia relative to the 534 subjects with asymptomatic or benign infection (P = 0.01). Experimental tests for all 118 rare nonsynonymous variants (including both pLOF and other variants) of these 13 genes found in patients with critical disease identified 23 patients (3.5%), aged 17 to 77 years, carrying 24 deleterious variants of eight genes. These variants underlie autosomal-recessive (AR) deficiencies (IRF7 and IFNAR1) and autosomal-dominant (AD) deficiencies (TLR3, UNC93B1, TICAM1, TBK1, IRF3, IRF7, IFNAR1, and IFNAR2) in four and 19 patients, respectively. These patients had never been hospitalized for other life-threatening viral illness. Plasmacytoid dendritic cells from IRF7-deficient patients produced no type I IFN on infection with SARS-CoV-2, and TLR3−/−, TLR3+/−, IRF7−/−, and IFNAR1−/− fibroblasts were susceptible to SARS-CoV-2 infection in vitro. CONCLUSION At least 3.5% of patients with life-threatening COVID-19 pneumonia had known (AR IRF7 and IFNAR1 deficiencies or AD TLR3, TICAM1, TBK1, and IRF3 deficiencies) or new (AD UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiencies) genetic defects at eight of the 13 candidate loci involved in the TLR3- and IRF7-dependent induction and amplification of type I IFNs. This discovery reveals essential roles for both the double-stranded RNA sensor TLR3 and type I IFN cell-intrinsic immunity in the control of SARS-CoV-2 infection. Type I IFN administration may be of therapeutic benefit in selected patients, at least early in the course of SARS-CoV-2 infection. Inborn errors of TLR3- and IRF7-dependent type I IFN production and amplification underlie life-threatening COVID-19 pneumonia. Molecules in red are encoded by core genes, deleterious variants of which underlie critical influenza pneumonia with incomplete penetrance, and deleterious variants of genes encoding biochemically related molecules in blue underlie other viral illnesses. Molecules represented in bold are encoded by genes with variants that also underlie critical COVID-19 pneumonia. Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)– and interferon regulatory factor 7 (IRF7)–dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

中文翻译：

危及生命的 COVID-19 患者 I 型干扰素免疫先天性缺陷

严重 COVID-19 的遗传学基础免疫系统很复杂，涉及许多基因，包括编码称为干扰素 (IFN) 的细胞因子的基因。缺乏特定干扰素的个体可能更容易感染传染病。此外，自身抗体系统会抑制干扰素反应，以防止病原体引起的炎症造成的损害。现在有两项研究探讨了遗传学通过该系统的组成部分影响 2019 年严重冠状病毒病 (COVID-19) 风险的可能性（参见 Beck 和 Aksentijevich 的观点）。问：张等人。使用候选基因方法，确定了患有严重 COVID-19 的患者，这些患者在涉及 I 型和 III 型 IFN 免疫调节的基因中存在突变。他们发现这些基因在患者体内富集，并得出结论：遗传学可能决定感染的临床过程。巴斯塔德等人。在大约 10% 的重症 COVID-19 肺炎患者中发现了具有高滴度的针对 I 型 IFN-α2 和 IFN-ω 的中和自身抗体的个体。在无症状或表型较轻的感染者或健康个体中都没有发现这些自身抗体。这些研究共同确定了一种方法，可用于识别危及生命的 COVID-19 风险最高的个体。科学，本期第 14 页。 eabd4570，p。 eabd4585;另见 p. 404 一项针对 COVID-19 患者的大型免疫学和基因组学研究揭示了 I 型 IFN 通路中的过度突变。简介人类严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染的临床结果范围从无症状感染到致命的 2019 冠状病毒病 (COVID-19)。流行病学研究确定了严重疾病的三个危险因素：男性、老年人和患有其他疾病。然而，每个人口类别的个体间临床变异仍然很大。发现危及生命的 COVID-19 的根本原因以及详细的分子、细胞、组织和身体层面的机制具有极其重要的生物学和医学意义。基本原理我们建立了 COVID 人类遗传努力 (www.covidhge.com)，以检验以下一般假设：部分或大多数患者中危及生命的 COVID-19 可能是由对 SARS-CoV-2 的单基因先天性免疫缺陷引起的，且不完全或不完整。完全渗透。我们对 659 名不同血统的危及生命的 COVID-19 肺炎患者和 534 名无症状或良性感染受试者的外显子组或基因组进行了测序。我们测试了特定的假设，即 Toll 样受体 3 (TLR3) 和干扰素调节因子 7 (IRF7) 依赖的 I 型干扰素 (IFN) 免疫先天性缺陷是危及生命的流感肺炎的基础，也是危及生命的 COVID-19 的基础肺炎。我们考虑了在危及生命的流感患者中确定为突变的三个位点：TLR3、IRF7 和 IRF9。我们还考虑了患有其他病毒性疾病的患者中的 10 个突变位点，但这些位点与赋予流感易感性的三个核心基因直接相关：来自 TLR3 依赖性 I 型 IFN 诱导途径的 TICAM1/TRIF、UNC93B1、TRAF3、TBK1、IRF3 和 NEMO/IKBKG ，以及来自 IRF7 和 IRF9 依赖性 I 型 IFN 扩增途径的 IFNAR1、IFNAR2、STAT1 和 STAT2。最后，我们考虑了这 13 个基因座的各种遗传模式。结果我们发现，与 534 例危及生命的 COVID-19 肺炎患者相比，在 659 例危及生命的 COVID-19 肺炎患者的 13 个候选基因座中，预测功能丧失 (pLOF) 的变异富集，次要等位基因频率为 <0.001。无症状或良性感染的受试者（P = 0.01）。对危重病患者中发现的这 13 个基因的所有 118 个罕见非同义变异（包括 pLOF 和其他变异）进行的实验测试发现，23 名年龄在 17 至 77 岁之间的患者（3.5%）携带 8 个基因的 24 个有害变异。这些变异分别是 4 名和 19 名患者的常染色体隐性 (AR) 缺陷（IRF7 和 IFNAR1）和常染色体显性 (AD) 缺陷（TLR3、UNC93B1、TICAM1、TBK1、IRF3、IRF7、IFNAR1 和 IFNAR2）的基础。这些患者从未因其他危及生命的病毒性疾病住院。 IRF7 缺陷患者的浆细胞样树突状细胞在感染 SARS-CoV-2 后不产生 I 型 IFN，并且 TLR3−/−、TLR3+/-、IRF7−/− 和 IFNAR1−/− 成纤维细胞对 SARS-CoV- 敏感2.体外感染。结论至少 3.5% 的危及生命的 COVID-19 肺炎患者已知（AR IRF7 和 IFNAR1 缺陷或 AD TLR3、TICAM1、TBK1 和 IRF3 缺陷）或新的（AD UNC93B1、IRF7、IFNAR1 和 IFNAR2 缺陷）遗传性13 个候选位点中有 8 个存在缺陷，这些位点参与 TLR3 和 IRF7 依赖的 I 型 IFN 诱导和扩增。这一发现揭示了双链 RNA 传感器 TLR3 和 I 型 IFN 细胞内在免疫在控制 SARS-CoV-2 感染中的重要作用。 I 型干扰素给药可能对选定的患者有治疗益处，至少在 SARS-CoV-2 感染过程的早期是如此。 TLR3 和 IRF7 依赖性 I 型 IFN 产生和扩增的先天性错误是危及生命的 COVID-19 肺炎的基础。红色分子由核心基因编码，其有害变异是外显率不完全的严重流感肺炎的基础，而编码蓝色生化相关分子的基因的有害变异是其他病毒性疾病的基础。以粗体表示的分子是由具有变异的基因编码的，这些变异也是严重的 COVID-19 肺炎的基础。严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 感染的临床结果范围从无症状感染到致命的 2019 冠状病毒病 (COVID-19)。我们发现，在已知控制 Toll 样受体 3 (TLR3) 和干扰素调节因子 7 (IRF7) 依赖性 I 型干扰素的 13 个人类基因座中，预计会出现功能丧失 (LOF) 的罕见变异富集。相对于 534 名无症状或良性感染受试者，659 名危及生命的 COVID-19 肺炎患者对流感病毒具有 IFN）免疫力。通过在这 13 个位点测试这些和其他罕见变异，我们在 23 名 17 至 77 岁患者 (3.5%) 中实验性地定义了常染色体隐性或常染色体显性缺陷的 LOF 变异。我们发现，具有影响该回路的突变的人类成纤维细胞很容易受到 SARS-CoV-2 的影响。对于既往没有严重感染的患者，TLR3 和 IRF7 依赖性 I 型 IFN 免疫的先天性错误可能是危及生命的 COVID-19 肺炎的基础。

更新日期：2020-09-24

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