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生命を脅かすCOVID-19患者におけるI型IFN免疫の先天性障害

Qian Zhang ¹, Paul Bastard ^2,3, Zhiyong Liu ¹

¹St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
²Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris, France.
³University of Paris, Imagine Institute, Paris, France.
⁴Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
⁵Department of Paediatric Infectious Diseases & Virology, Imperial College London, London, UK.
⁶Yale Center for Genome Analysis and Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
⁷Zukerman Mind Brain Behavior Institute, Columbia University, New York, NY, USA.
⁸Helix, San Mateo, CA, USA.
⁹Primary Immunodeficiencies Group, University of Antioquia UdeA, Medellin, Colombia.
¹⁰School of Microbiology, University of Antioquia UdeA, Medellin, Colombia.
¹¹Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, NIAID, NIH, Bethesda, MD, USA.
¹²NIAID Clinical Genomics Program, NIH, Bethesda, MD, USA.
¹³Université de Paris, Institut de Recherche Saint-Louis, INSERM U976, Hôpital Saint-Louis, Paris, France.
¹⁴Laboratory of Genomes & Cell Biology of Disease, INSERM U944, CNRS UMR 7212, Université de Paris, Institut de Recherche Saint-Louis, Hôpital Saint-Louis, Paris, France.
¹⁵Sorbonne Université, Inserm, Centre d'Immunologie et des Maladies Infectieuses-Paris (CIMI PARIS), Assistance Publique-Hôpitaux de Paris (AP-HP) Hôpital Pitié-Salpêtrière, Paris, France.
¹⁶Translational Immunology Lab, Institut Pasteur, Paris, France.
¹⁷Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
¹⁸Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹Sorbonne Université, UMS037, PASS, Plateforme de Cytométrie de la Pitié-Salpêtrière CyPS, Paris, France.
²⁰Bioinformatics Platform, Structure Fédérative de Recherche Necker, INSERM UMR1163, Université de Paris, Imagine Institute, Paris, France.
²¹Neurometabolic Diseases Laboratory, IDIBELL-Hospital Duran i Reynals, CIBERER U759, and Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
²²Department of Immunology, Research Branch, Sidra Medicine, Doha, Qatar.
²³School of Life sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
²⁴Precision Medicine Unit, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
²⁵Swiss Institue of Bioinformatics, Lausanne, Switzerland.
²⁶Infectious Disease Susceptibility Program, Research Institute, McGill University Health Centre, Montréal, Québec, Canada.
²⁷Specialized Immunology Laboratory of Dr. Shahrooei, Sina Medical Complex, Ahvaz, Iran.
²⁸Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven, Leuven, Belgium.
²⁹Department of Pathology and Laboratory Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
³⁰Department of Clinical Immunology and Infectious Diseases, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
³¹The 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.
³²Pediatric Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti, Iran.
³³National Center of Genomics Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.
³⁴Dasman Diabetes Institute, Department of Genetics and Bioinformatics, Kuwait.
³⁵Immunology Research Laboratory, Department of Pediatrics, College of Medicine and King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
³⁶Translational Pathology, Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City, Misery of National Guard Health Affairs, Riyadh, Saudi Arabia.
³⁷Cancer & Blood Research, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
³⁸Amsterdam UMC, Department of Neurology, Amsterdam Neuroscience, Amsterdam, Netherlands.
³⁹Pediatric Departement and Centro Tettamanti-European Reference Network PaedCan, EuroBloodNet, MetabERN-University of Milano-Bicocca-Fondazione MBBM-Ospedale, San Gerardo, Monza, Italy.
⁴⁰Department of Infectious Diseases, San Gerardo Hospital-University of Milano-Bicocca, Monza, Italy.
⁴¹CREA Laboratory, Diagnostic Laboratory, ASST Spedali Civili di Brescia, Brescia, Italy.
⁴²Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali di Brescia, Brescia, Italy.
⁴³Chief Medical Officer, ASST Spedali Civili di Brescia, Brescia, Italy.
⁴⁴Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD, USA.
⁴⁵PRIMER, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁴⁶Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
⁴⁷Department of Internal Medicine, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
⁴⁸Fonds de la Recherche Scientifique (FNRS) and Center of Human Genetics, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
⁴⁹Department 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.
⁵⁰Pediatric 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.
⁵¹Immunology Division, Genetics Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute, Vall d'Hebron Barcelona Hospital Campus, UAB, Barcelona, Catalonia, Spain.
⁵²Aix Marseille Univ, INSERM, INRAE, C2VN, CHU Timone, Marseille, France.
⁵³Necmettin Erbakan University, Meram Medical Faculty, Division of Pediatric Allergy and Immunology, Konya, Turkey.
⁵⁴Department of Infectious Diseases and Clinical Microbiology, Konya Training and Research Hospital, Konya, Turkey.
⁵⁵Department of Molecular Biology and Genetics, Bilkent University, Bilkent-Ankara, Turkey.
⁵⁶Departments of Infectious Diseases and Clinical Microbiology, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey.
⁵⁷Department of Immunology, Hospital Universitario de G.C. Dr. Negrín, Canarian Health System, Las Palmas de Gran Canaria, Spain.
⁵⁸University Fernando Pessoa Canarias, Las Palmas de Gran Canaria, Spain.
⁵⁹Department of Biomedicine and Prevention, University of Rome "Tor Vergata," Rome, Italy.
⁶⁰Intensive Care Unit, AP-HM, Marseille, France.
⁶¹Avicenne Hospital Intensive Care Unit, APHP, Bobigny, INSERM U1272 Hypoxia & Lung, Paris, France.
⁶²PH Réanimation CHU Avicenne, Bobigny, INSERM U1272 Hypoxie & Poumon, Paris, France.
⁶³Université de Paris, IAME UMR-S 1137, INSERM, Paris, France.
⁶⁴Inserm CIC 1425, Paris, France.
⁶⁵AP-HP, Département Epidémiologie Biostatistiques et Recherche Clinique, Hôpital Bichat, Paris, France.
⁶⁶Department of Pharmacology & Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁶⁷Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁶⁸Division of Pediatric Allergy, Immunology and Rheumatology, Columbia University, New York, USA.
⁶⁹Department of Infectious Diseases, Aarhus University Hospital, Skejby, Denmark.
⁷⁰Department of Biomedicine, Aarhus University, Aarhus, Denmark.
⁷¹College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁷²Department of Medical Microbiology, Utrecht UMC, Utrecht, Netherlands.
⁷³Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Paris, France.
⁷⁴Turnstone Biologics, New York, NY, USA.
⁷⁵Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.
⁷⁶New York Genome Center, New York, NY, USA.
⁷⁷AP-HP, Hôpital Saint-Louis, Laboratoire d'Immunologie, Paris, France.
⁷⁸Laboratory of Molecular Immunology, Rockefeller University, New York, NY, USA.
⁷⁹Howard Hughes Medical Institute, New York, NY, USA.
⁸⁰Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸¹Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸²The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸³Laboratory of Genetics and Genomics, The Rockefeller University, New York, NY, USA.
⁸⁴Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
⁸⁵Yale Center for Genome Analysis, Yale School of Medicine, New Haven, CT, USA.
⁸⁶St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. casanova@rockefeller.edu.
⁸⁷Pediatric Hematology and Immunology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.

⁰St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.

Science (New York, N.Y.) +

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2020年9月25日

PubMedで要約を見る

まとめ

トール型受容体3 (TLR3) とインターフェロン調節因子7 (IRF7) の免疫における遺伝的欠陥は,生命を脅かすCOVID-19肺炎のリスクを高めます. これらの稀な機能障害の変種は,以前に感染していなくても重篤な病気を引き起こす可能性があります.

科学分野

免疫学
遺伝学
ウイルス学

背景

重症急性呼吸器症候群コロナウイルス2型 (SARS-CoV-2型) は,無症状から致死性コロナウイルス病2019型 (COVID-19) まで,さまざまな疾患を引き起こす.
I型インターフェロン (IFN) 免疫,特にトール型受容体3 (TLR3) とインターフェロン調節因子7 (IRF7) に依存する経路は,インフルエンザウイルスに対する抗ウイルス防御に不可欠です.

研究の目的

重度のCOVID-19肺炎患者のTLR3およびIRF7依存型I型IFN免疫における遺伝子変異の役割を調査する.
特定の機能喪失 (LOF) 変種を特定し,個人を生命を脅かすCOVID-19に易感させる.

主な方法

TLR3およびIRF7依存型のIFN免疫を制御する13のヒトの稀な変異の分析.
重度のCOVID-19肺炎と無症状または良性感染症の患者の間の変異頻度の比較.
患者に由来する線維芽細胞におけるLOF変異の実験的検証とSARS-CoV-2の脆弱性の評価.

主要な成果

重度のCOVID-19肺炎の患者では,対照群と比較して,TLR3およびIRF7依存型I型IFN免疫を調節する遺伝子の稀なLOF変異の濃縮が観察されました.
実験的に定義されたLOF変種の欠陥は,重症なCOVID-19患者の3.5%で特定されました.
この免疫回路に変異があるヒトの線維芽細胞は,SARS-CoV-2感染に対する脆弱性の高まりを示した.

結論

TLR3およびIRF7依存型I型IFN免疫における先天的な誤差は,生命を脅かすCOVID-19肺炎の原因である可能性があります.
これらの遺伝的欠陥は,以前の重篤な感染に関係なく,SARS-CoV-2感染による重篤なアウトカムに個人を誘発する可能性があります.
これらの遺伝的基盤を理解することはリスクのある集団を特定し標的を絞った介入策を策定する上で極めて重要です

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