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COVID-19の組織アトラスは,SARS-CoV-2の病理および細胞標的を明らかにする.

Toni M Delorey ¹, Carly G K Ziegler ^2,3,4,5,6,7, Graham Heimberg ¹

¹Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³Program in Health Sciences & Technology, Harvard Medical School and Massachusetts Institute of Technology, Boston, MA, USA.
⁴Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA.
⁷Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA.
⁸Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁹Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁰Harvard Medical School, Boston, MA, USA.
¹¹Massachusetts Institute of Technology, Cambridge, MA, USA.
¹²Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹³Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴Department of Epidemiology, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA.
¹⁵Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹⁶Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹⁷Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
¹⁸Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA.
¹⁹Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.
²⁰Department of Medicine, Division of Hematology/Oncology, Columbia University Irving Medical Center, New York, NY, USA.
²¹Columbia Center for Translational Immunology, New York, NY, USA.
²²Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²³Institute for Molecular Medicine Finland, Helsinki, Finland.
²⁴Analytical & Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
²⁵Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA.
²⁶Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
²⁷Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
²⁸Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
²⁹FAS Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
³⁰Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³¹Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core Boston, Boston, MA, USA.
³²Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA, USA.
³³Divisions of Cardiovascular Medicine and Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
³⁴NanoString Technologies Inc, Seattle, WA, USA.
³⁵Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
³⁶Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³⁷Department of Genetics and BASE Initiative, Stanford University School of Medicine, Stanford, CA, USA.
³⁸Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
³⁹Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴⁰Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁴¹John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
⁴²Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, USA.
⁴³Department of Pathology, Harvard Medical School, Boston, MA, USA.
⁴⁴Harvard Stem Cell Institute, Cambridge, MA, USA.
⁴⁵Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁴⁶Infectious Diseases Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁷Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁴⁸Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA.
⁴⁹Cardiovascular Disease Initiative, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵⁰Department of Genetics, Harvard Medical School, Boston, MA, USA.
⁵¹Department of Molecular Biology and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA, USA.
⁵²Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁵³Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁵⁴Massachusetts Consortium on Pathogen Readiness, Boston, MA, USA.
⁵⁵Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
⁵⁶Massachusetts General Hospital, Boston, MA, USA.
⁵⁷Vascular Biology Program and Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁵⁸Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.
⁵⁹Program for Mathematical Genomics, Columbia University Irving Medical Center, New York, NY, USA.
⁶⁰Broad Institute of MIT and Harvard, Cambridge, MA, USA. ivlachos@bidmc.harvard.edu.
⁶¹Harvard Medical School, Boston, MA, USA. ivlachos@bidmc.harvard.edu.
⁶²Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. ivlachos@bidmc.harvard.edu.
⁶³Harvard Medical School Initiative for RNA Medicine, Boston, MA, USA. ivlachos@bidmc.harvard.edu.
⁶⁴Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA. ivlachos@bidmc.harvard.edu.
⁶⁵Broad Institute of MIT and Harvard, Cambridge, MA, USA. shalek@mit.edu.
⁶⁶Program in Health Sciences & Technology, Harvard Medical School and Massachusetts Institute of Technology, Boston, MA, USA. shalek@mit.edu.
⁶⁷Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu.
⁶⁸Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu.
⁶⁹Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA. shalek@mit.edu.
⁷⁰Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA, USA. shalek@mit.edu.
⁷¹Harvard Medical School, Boston, MA, USA. shalek@mit.edu.
⁷²Harvard Stem Cell Institute, Cambridge, MA, USA. shalek@mit.edu.
⁷³Program in Computational & Systems Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu.
⁷⁴Program in Immunology, Harvard Medical School, Boston, MA, USA. shalek@mit.edu.
⁷⁵Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. shalek@mit.edu.
⁷⁶Broad Institute of MIT and Harvard, Cambridge, MA, USA. avillani@mgh.harvard.edu.
⁷⁷Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. avillani@mgh.harvard.edu.
⁷⁸Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. avillani@mgh.harvard.edu.
⁷⁹Department of Medicine, Harvard Medical School, Boston, MA, USA. avillani@mgh.harvard.edu.
⁸⁰Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. orit.r.rosen@gmail.com.
⁸¹Genentech, South San Francisco, CA, USA. orit.r.rosen@gmail.com.
⁸²Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aviv.regev.sc@gmail.com.
⁸³Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. aviv.regev.sc@gmail.com.
⁸⁴Howard Hughes Medical Institute, Chevy Chase, MD, USA. aviv.regev.sc@gmail.com.
⁸⁵Genentech, South San Francisco, CA, USA. aviv.regev.sc@gmail.com.

⁰Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Nature +

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2021年4月29日

PubMedで要約を見る

まとめ

この研究は,SARS-CoV-2感染が肺組織を改造し,再生が失敗し,心臓のような他の臓器に影響を及ぼすことを明らかにしています. これらのCOVID-19の影響を理解することは,新しい治療法の開発に不可欠です.

科学分野

重度のSARS-CoV-2感染の病理生理学
COVID-19に対する臓器特有の細胞および分子反応

背景

重症急性呼吸器症候群-コロナウイルス-2 (SARS-CoV-2) はCOVID-19を引き起こすため,急性呼吸器症候群および多臓器不全を引き起こす.
複数の臓器におけるSARS-CoV-2感染の詳細な病理生理学と細胞上の影響は,まだ完全に理解されていません.

研究の目的

COVID-19 死亡者からの解剖組織の包括的な単細胞および空間アトラスを生成する.
重度のCOVID-19で臓器損傷と再生の失敗の原因となる細胞および分子メカニズムを解明する.

主な方法

肺,腎臓,肝臓,心臓の解剖サンプルから単細胞アトラスの生成.
肺組織のための空間アトラスの作成
細胞再構成と宿主応答を特定するためのマルチオームデータの統合計算分析.

主要な成果

肺上皮質,免疫系,および筋膜の重組が確認され,組織再生が失敗した証拠がある.
特定の肺細胞 (単核ファゴサイト,内皮細胞) でのウイルスのRNAの濃縮が観察され,異なる宿主反応を誘発する.
ゲノム全体の関連性研究を用いて,心臓組織における転写変異を検出し,COVID-19の重症度に関連した細胞タイプ/遺伝子をマッピングした.

結論

重度のSARS-CoV-2感染が複数の臓器に及ぼす生物学的影響を明らかにする基本データセットを提供します.
肺の再生に失敗したメカニズムとして,欠陥のあるアルベオラ型2細胞の分化と原始細胞の膨張を強調する.
臓器特異的な損傷と宿主反応に関する洞察を提供し,重度のCOVID-19に対する新しい治療戦略の道を開いています.