Exuberant fibroblast activity compromises lung function via ADAMTS4

David F Boyd; E Kaitlynn Allen; Adrienne G Randolph; Xi-Zhi J Guo; Yunceng Weng; Catherine J Sanders; Resha Bajracharya; Natalie K Lee; Clifford S Guy; Peter Vogel; Wenda Guan; Yimin Li; Xiaoqing Liu; Tanya Novak; Margaret M Newhams; Thomas P Fabrizio; Nicholas Wohlgemuth; Peter M Mourani; Thomas N Wight; Stacey Schultz-Cherry; Stephania A Cormier; Kathryn Shaw-Saliba; Andrew Pekosz; Richard E Rothman; Kuan-Fu Chen; Zifeng Yang; Richard J Webby; Nanshan Zhong; Jeremy Chase Crawford; Paul G Thomas; PALISI Pediatric Intensive Care Influenza (PICFLU) Investigators

doi:10.1038/s41586-020-2877-5

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Exuberant fibroblast activity compromises lung function via ADAMTS4

Journal article

Open access

Peer reviewed

Exuberant fibroblast activity compromises lung function via ADAMTS4

David F Boyd, E Kaitlynn Allen, Adrienne G Randolph, Xi-Zhi J Guo, Yunceng Weng, Catherine J Sanders, Resha Bajracharya, Natalie K Lee, Clifford S Guy, Peter Vogel, …

Nature (London), Vol.587(7834), pp.466-471

2020-11

DOI: https://doi.org/10.1038/s41586-020-2877-5

PMID: 33116313

Abstract

ADAMTS4 Protein - antagonists & inhibitors

ADAMTS4 Protein - metabolism

Animals

Birds - virology

Extracellular Matrix - enzymology

Fibroblasts - enzymology

Fibroblasts - pathology

Gene Expression Profiling

Humans

Influenza A virus - pathogenicity

Influenza in Birds - virology

Influenza, Human - pathology

Influenza, Human - therapy

Influenza, Human - virology

Interferons - immunology

Interferons - metabolism

Leukocyte Common Antigens - metabolism

Lung - enzymology

Lung - pathology

Lung - physiopathology

Lung - virology

Mice

Respiratory Distress Syndrome - enzymology

Respiratory Distress Syndrome - physiopathology

Respiratory Distress Syndrome - therapy

Respiratory Distress Syndrome - virology

Seasons

Single-Cell Analysis

Stromal Cells - metabolism

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS) . There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS . Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.54 Molecular & Cell Biology - Genetics; 1.54.1543 RNA-Seq
Web Of Science research areas: Multidisciplinary Sciences
ESI research areas: Clinical Medicine

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Title: Exuberant fibroblast activity compromises lung function via ADAMTS4
Creators: David F Boyd - Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
E Kaitlynn Allen - Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
Adrienne G Randolph - Department of Anesthesia, Harvard Medical School, Boston, MA, USA
Xi-Zhi J Guo - Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
Yunceng Weng - State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Catherine J Sanders - Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
Resha Bajracharya - Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
Natalie K Lee - Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA
Clifford S Guy - Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
Peter Vogel - Veterinary Pathology Core, St Jude Children's Research Hospital, Memphis, TN, USA
Wenda Guan - State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Yimin Li - State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Xiaoqing Liu - State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Tanya Novak - Department of Anesthesia, Harvard Medical School, Boston, MA, USA
Margaret M Newhams - Boston Children's Hospital, Department of Anesthesiology, Critical Care and Pain Medicine, Boston, MA, USA
Thomas P Fabrizio - Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA
Nicholas Wohlgemuth - Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA
Peter M Mourani - Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA
Thomas N Wight - Matrix Biology Program, Benaroya Research Institute, Seattle, WA, USA
Stacey Schultz-Cherry - Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA
Stephania A Cormier - Pennington Biomedical Research Center, Baton Rouge, LA, USA
Kathryn Shaw-Saliba - Department of Emergency Medicine and Medicine, Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Andrew Pekosz - Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
Richard E Rothman - Department of Emergency Medicine and Medicine, Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Kuan-Fu Chen - Clinical Informatics and Medical Statistics Research Center of Chang Gung University, Taoyuan, Taiwan
Zifeng Yang - State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Richard J Webby - Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA
Nanshan Zhong - State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
Jeremy Chase Crawford - Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
Paul G Thomas - Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA. paul.thomas@stjude.org
PALISI Pediatric Intensive Care Influenza (PICFLU) Investigators
Publication Details: Nature (London), Vol.587(7834), pp.466-471
Grant note: R01 AI084011 / NIAID NIH HHS U42 OD011158 / NIH HHS HHSN272201400006C / NIAID NIH HHS R01 AI128805 / NIAID NIH HHS HHSN272201400007C / NIAID NIH HHS R21 HD095228 / NICHD NIH HHS
Language: English
Resource Type: Journal article
PMID: 33116313
Record Identifier: 991031613455802976