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COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets

Author

Listed:
  • Toni M. Delorey

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Carly G. K. Ziegler

    (Broad Institute of MIT and Harvard
    Harvard Medical School and Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Graham Heimberg

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Rachelly Normand

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital, Harvard Medical School
    Harvard Medical School)

  • Yiming Yang

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Åsa Segerstolpe

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Domenic Abbondanza

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Stephen J. Fleming

    (Data Sciences Platform, Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Ayshwarya Subramanian

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Daniel T. Montoro

    (Broad Institute of MIT and Harvard)

  • Karthik A. Jagadeesh

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Kushal K. Dey

    (Harvard T. H. Chan School of Public Health, Harvard University)

  • Pritha Sen

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital
    Harvard Medical School)

  • Michal Slyper

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Yered H. Pita-Juárez

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Beth Israel Deaconess Medical Center
    Harvard Medical School Initiative for RNA Medicine)

  • Devan Phillips

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Jana Biermann

    (Division of Hematology/Oncology, Columbia University Irving Medical Center
    Columbia Center for Translational Immunology)

  • Zohar Bloom-Ackermann

    (Broad Institute of MIT and Harvard)

  • Nikolaos Barkas

    (Data Sciences Platform, Broad Institute of MIT and Harvard)

  • Andrea Ganna

    (Institute for Molecular Medicine Finland
    Analytical & Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School)

  • James Gomez

    (Broad Institute of MIT and Harvard)

  • Johannes C. Melms

    (Division of Hematology/Oncology, Columbia University Irving Medical Center
    Columbia Center for Translational Immunology)

  • Igor Katsyv

    (Columbia University Irving Medical Center)

  • Erica Normandin

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Pourya Naderi

    (Harvard Medical School
    Beth Israel Deaconess Medical Center
    Harvard Medical School Initiative for RNA Medicine)

  • Yury V. Popov

    (Harvard Medical School
    Beth Israel Deaconess Medical Center
    Beth Israel Deaconess Medical Center)

  • Siddharth S. Raju

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Harvard University)

  • Sebastian Niezen

    (Harvard Medical School
    Beth Israel Deaconess Medical Center
    Beth Israel Deaconess Medical Center)

  • Linus T.-Y. Tsai

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Beth Israel Deaconess Medical Center
    Beth Israel Deaconess Medical Center)

  • Katherine J. Siddle

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Malika Sud

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Victoria M. Tran

    (Broad Institute of MIT and Harvard)

  • Shamsudheen K. Vellarikkal

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Yiping Wang

    (Division of Hematology/Oncology, Columbia University Irving Medical Center
    Columbia Center for Translational Immunology)

  • Liat Amir-Zilberstein

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Deepak S. Atri

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Joseph Beechem

    (NanoString Technologies Inc)

  • Olga R. Brook

    (Beth Israel Deaconess Medical Center)

  • Jonathan Chen

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital, Harvard Medical School)

  • Prajan Divakar

    (NanoString Technologies Inc)

  • Phylicia Dorceus

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Jesse M. Engreitz

    (Broad Institute of MIT and Harvard
    Stanford University School of Medicine)

  • Adam Essene

    (Beth Israel Deaconess Medical Center
    Beth Israel Deaconess Medical Center
    Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core Boston)

  • Donna M. Fitzgerald

    (Massachusetts General Hospital)

  • Robin Fropf

    (NanoString Technologies Inc)

  • Steven Gazal

    (University of Southern California)

  • Joshua Gould

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Data Sciences Platform, Broad Institute of MIT and Harvard)

  • John Grzyb

    (Brigham and Women’s Hospital)

  • Tyler Harvey

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Jonathan Hecht

    (Harvard Medical School
    Beth Israel Deaconess Medical Center)

  • Tyler Hether

    (NanoString Technologies Inc)

  • Judit Jané-Valbuena

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Michael Leney-Greene

    (Broad Institute of MIT and Harvard)

  • Hui Ma

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Massachusetts General Hospital)

  • Cristin McCabe

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Daniel E. McLoughlin

    (Massachusetts General Hospital)

  • Eric M. Miller

    (NanoString Technologies Inc)

  • Christoph Muus

    (Broad Institute of MIT and Harvard
    Harvard University)

  • Mari Niemi

    (Institute for Molecular Medicine Finland)

  • Robert Padera

    (Brigham and Women’s Hospital
    Harvard-MIT Division of Health Sciences and Technology
    Harvard Medical School)

  • Liuliu Pan

    (NanoString Technologies Inc)

  • Deepti Pant

    (Beth Israel Deaconess Medical Center
    Beth Israel Deaconess Medical Center
    Boston Nutrition and Obesity Research Center Functional Genomics and Bioinformatics Core Boston)

  • Carmel Pe’er

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Jenna Pfiffner-Borges

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Christopher J. Pinto

    (Harvard Medical School
    Massachusetts General Hospital)

  • Jacob Plaisted

    (Brigham and Women’s Hospital)

  • Jason Reeves

    (NanoString Technologies Inc)

  • Marty Ross

    (NanoString Technologies Inc)

  • Melissa Rudy

    (Broad Institute of MIT and Harvard)

  • Erroll H. Rueckert

    (NanoString Technologies Inc)

  • Michelle Siciliano

    (Brigham and Women’s Hospital)

  • Alexander Sturm

    (Broad Institute of MIT and Harvard)

  • Ellen Todres

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Avinash Waghray

    (Harvard Stem Cell Institute
    Massachusetts General Hospital)

  • Sarah Warren

    (NanoString Technologies Inc)

  • Shuting Zhang

    (Broad Institute of MIT and Harvard)

  • Daniel R. Zollinger

    (NanoString Technologies Inc)

  • Lisa Cosimi

    (Brigham and Women’s Hospital)

  • Rajat M. Gupta

    (Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Nir Hacohen

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital, Harvard Medical School
    Harvard Medical School)

  • Hanina Hibshoosh

    (Columbia University Irving Medical Center)

  • Winston Hide

    (Harvard Medical School
    Beth Israel Deaconess Medical Center
    Harvard Medical School Initiative for RNA Medicine
    Beth Israel Deaconess Medical Center)

  • Alkes L. Price

    (Harvard T. H. Chan School of Public Health, Harvard University)

  • Jayaraj Rajagopal

    (Massachusetts General Hospital)

  • Purushothama Rao Tata

    (Duke University School of Medicine)

  • Stefan Riedel

    (Harvard Medical School
    Beth Israel Deaconess Medical Center)

  • Gyongyi Szabo

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Beth Israel Deaconess Medical Center)

  • Timothy L. Tickle

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Data Sciences Platform, Broad Institute of MIT and Harvard)

  • Patrick T. Ellinor

    (Broad Institute of MIT and Harvard)

  • Deborah Hung

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Massachusetts General Hospital)

  • Pardis C. Sabeti

    (Broad Institute of MIT and Harvard
    Harvard University
    Harvard University
    Howard Hughes Medical Institute)

  • Richard Novak

    (Harvard University)

  • Robert Rogers

    (Beth Israel Deaconess Medical Center
    Massachusetts General Hospital)

  • Donald E. Ingber

    (Harvard University
    Harvard University
    Boston Children’s Hospital, Harvard Medical School)

  • Z. Gordon Jiang

    (Harvard Medical School
    Beth Israel Deaconess Medical Center
    Beth Israel Deaconess Medical Center)

  • Dejan Juric

    (Harvard Medical School
    Massachusetts General Hospital)

  • Mehrtash Babadi

    (Data Sciences Platform, Broad Institute of MIT and Harvard
    Broad Institute of MIT and Harvard)

  • Samouil L. Farhi

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Benjamin Izar

    (Division of Hematology/Oncology, Columbia University Irving Medical Center
    Columbia Center for Translational Immunology
    Columbia University Irving Medical Center
    Columbia University Irving Medical Center)

  • James R. Stone

    (Massachusetts General Hospital, Harvard Medical School)

  • Ioannis S. Vlachos

    (Broad Institute of MIT and Harvard
    Harvard Medical School
    Beth Israel Deaconess Medical Center
    Harvard Medical School Initiative for RNA Medicine)

  • Isaac H. Solomon

    (Brigham and Women’s Hospital)

  • Orr Ashenberg

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Caroline B. M. Porter

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard)

  • Bo Li

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Harvard Medical School)

  • Alex K. Shalek

    (Broad Institute of MIT and Harvard
    Harvard Medical School and Massachusetts Institute of Technology
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Alexandra-Chloé Villani

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital
    Massachusetts General Hospital, Harvard Medical School
    Harvard Medical School)

  • Orit Rozenblatt-Rosen

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Genentech)

  • Aviv Regev

    (Klarman Cell Observatory, Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology
    Howard Hughes Medical Institute
    Genentech)

Abstract

COVID-19, which is caused by SARS-CoV-2, can result in acute respiratory distress syndrome and multiple organ failure1–4, but little is known about its pathophysiology. Here we generated single-cell atlases of 24 lung, 16 kidney, 16 liver and 19 heart autopsy tissue samples and spatial atlases of 14 lung samples from donors who died of COVID-19. Integrated computational analysis uncovered substantial remodelling in the lung epithelial, immune and stromal compartments, with evidence of multiple paths of failed tissue regeneration, including defective alveolar type 2 differentiation and expansion of fibroblasts and putative TP63+ intrapulmonary basal-like progenitor cells. Viral RNAs were enriched in mononuclear phagocytic and endothelial lung cells, which induced specific host programs. Spatial analysis in lung distinguished inflammatory host responses in lung regions with and without viral RNA. Analysis of the other tissue atlases showed transcriptional alterations in multiple cell types in heart tissue from donors with COVID-19, and mapped cell types and genes implicated with disease severity based on COVID-19 genome-wide association studies. Our foundational dataset elucidates the biological effect of severe SARS-CoV-2 infection across the body, a key step towards new treatments.

Suggested Citation

  • Toni M. Delorey & Carly G. K. Ziegler & Graham Heimberg & Rachelly Normand & Yiming Yang & Åsa Segerstolpe & Domenic Abbondanza & Stephen J. Fleming & Ayshwarya Subramanian & Daniel T. Montoro & Karth, 2021. "COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets," Nature, Nature, vol. 595(7865), pages 107-113, July.
    • Handle: RePEc:nat:nature:v:595:y:2021:i:7865:d:10.1038_s41586-021-03570-8
    DOI: 10.1038/s41586-021-03570-8
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    Cited by:

    1. Shelly J. Robertson & Olivia Bedard & Kristin L. McNally & Carl Shaia & Chad S. Clancy & Matthew Lewis & Rebecca M. Broeckel & Abhilash I. Chiramel & Jeffrey G. Shannon & Gail L. Sturdevant & Rebecca , 2023. "Genetically diverse mouse models of SARS-CoV-2 infection reproduce clinical variation in type I interferon and cytokine responses in COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Christina Beck & Deepak Ramanujam & Paula Vaccarello & Florenc Widenmeyer & Martin Feuerherd & Cho-Chin Cheng & Anton Bomhard & Tatiana Abikeeva & Julia Schädler & Jan-Peter Sperhake & Matthias Graw &, 2023. "Trimannose-coupled antimiR-21 for macrophage-targeted inhalation treatment of acute inflammatory lung damage," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Laura Heydemann & Małgorzata Ciurkiewicz & Georg Beythien & Kathrin Becker & Klaus Schughart & Stephanie Stanelle-Bertram & Berfin Schaumburg & Nancy Mounogou-Kouassi & Sebastian Beck & Martin Zickler, 2023. "Hamster model for post-COVID-19 alveolar regeneration offers an opportunity to understand post-acute sequelae of SARS-CoV-2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Yanhua Li & Shijie Qin & Lei Dong & Shitong Qiao & Xiao Wang & Dongshan Yu & Pengyue Gao & Yali Hou & Shouzhen Quan & Ying Li & Fengyan Fan & Xin Zhao & Yueyun Ma & George Fu Gao, 2024. "Long-term effects of Omicron BA.2 breakthrough infection on immunity-metabolism balance: a 6-month prospective study," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    5. Tabea M. Eser & Olga Baranov & Manuel Huth & Mohammed I. M. Ahmed & Flora Deák & Kathrin Held & Luming Lin & Kami Pekayvaz & Alexander Leunig & Leo Nicolai & Georgios Pollakis & Marcus Buggert & David, 2023. "Nucleocapsid-specific T cell responses associate with control of SARS-CoV-2 in the upper airways before seroconversion," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. Kuei-Pin Chung & Chih-Ning Cheng & Yi-Jung Chen & Chia-Lang Hsu & Yen-Lin Huang & Min-Shu Hsieh & Han-Chun Kuo & Ya-Ting Lin & Yi-Hsiu Juan & Kiichi Nakahira & Yen-Fu Chen & Wei-Lun Liu & Sheng-Yuan R, 2024. "Alveolar epithelial cells mitigate neutrophilic inflammation in lung injury through regulating mitochondrial fatty acid oxidation," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    7. Maik Pietzner & Robert Lorenz Chua & Eleanor Wheeler & Katharina Jechow & Julian D. S. Willett & Helena Radbruch & Saskia Trump & Bettina Heidecker & Hugo Zeberg & Frank L. Heppner & Roland Eils & Mar, 2022. "ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Praveen Weeratunga & Laura Denney & Joshua A. Bull & Emmanouela Repapi & Martin Sergeant & Rachel Etherington & Chaitanya Vuppussetty & Gareth D. H. Turner & Colin Clelland & Jeongmin Woo & Amy Cross , 2023. "Single cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    9. Junedh M. Amrute & Alexandra M. Perry & Gautam Anand & Carlos Cruchaga & Karl G. Hock & Christopher W. Farnsworth & Gwendalyn J. Randolph & Kory J. Lavine & Ashley L. Steed, 2022. "Cell specific peripheral immune responses predict survival in critical COVID-19 patients," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    10. Pablo Jané & Xiaoying Xu & Vincent Taelman & Eduardo Jané & Karim Gariani & Rebecca A. Dumont & Yonathan Garama & Francisco Kim & María Val Gomez & Martin A. Walter, 2023. "The Imageable Genome," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    11. Erik Duijvelaar & Jack Gisby & James E. Peters & Harm Jan Bogaard & Jurjan Aman, 2024. "Longitudinal plasma proteomics reveals biomarkers of alveolar-capillary barrier disruption in critically ill COVID-19 patients," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    12. Xiaolei Wang & Terrence Tsz-Tai Yuen & Ying Dou & Jingchu Hu & Renhao Li & Zheng Zeng & Xuansheng Lin & Huarui Gong & Celia Hoi-Ching Chan & Chaemin Yoon & Huiping Shuai & Deborah Tip-Yin Ho & Ivan Fa, 2023. "Vaccine-induced protection against SARS-CoV-2 requires IFN-γ-driven cellular immune response," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    13. Benjamin Ng & Kevin Y. Huang & Chee Jian Pua & Sivakumar Viswanathan & Wei-Wen Lim & Fathima F. Kuthubudeen & Yu-Ning Liu & An An Hii & Benjamin L. George & Anissa A. Widjaja & Enrico Petretto & Stuar, 2024. "Interleukin-11 causes alveolar type 2 cell dysfunction and prevents alveolar regeneration," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    14. Ronja Mothes & Anna Pascual-Reguant & Ralf Koehler & Juliane Liebeskind & Alina Liebheit & Sandy Bauherr & Lars Philipsen & Carsten Dittmayer & Michael Laue & Regina Manitius & Sefer Elezkurtaj & Pawe, 2023. "Distinct tissue niches direct lung immunopathology via CCL18 and CCL21 in severe COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Xin Pan & Lan Wang & Juntang Yang & Yingge Li & Min Xu & Chenxi Liang & Lulu Liu & Zhongzheng Li & Cong Xia & Jiaojiao Pang & Mengyuan Wang & Meng Li & Saiya Guo & Peishuo Yan & Chen Ding & Ivan O. Ro, 2024. "TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    16. Urban Lendahl & Lars Muhl & Christer Betsholtz, 2022. "Identification, discrimination and heterogeneity of fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    17. Tomoko Nakanishi & Julian Willett & Yossi Farjoun & Richard J. Allen & Beatriz Guillen-Guio & Darin Adra & Sirui Zhou & J. Brent Richards, 2023. "Alternative splicing in lung influences COVID-19 severity and respiratory diseases," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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