Abstract
Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. 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 ARDS1,2. 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 466-471 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 587 |
| Issue number | 7834 |
| DOIs | |
| State | Published - Nov 19 2020 |
Funding
For lung samples from de-identified, deceased donors, the tissues utilized were procured by the National Disease Research Interchange (NDRI) with support from NIH grant U42OD11158. All NDRI consent forms and protocols are reviewed and approved by the Institutional Review Board at the University of Pennsylvania. Research involving these tissues was determined to not involve human subjects by the Institutional Review Board at St. Jude Children’s Research Hospital. Acknowledgements We thank the participants in each of the cohorts included in this study; H. Zhou, L.-A. Van De Velde, A. Souquette, G. Lennon and D. You for technical assistance in conducting experiments; T. Flerlage for critical reading of the manuscript; and the St Jude Animal Resource Center for the care of the animals used in this study. We acknowledge the use of tissues procured by the NDRI with support from NIH grant U42OD11158. Schematics in figures were made using an academic license of Biorender software. This work was funded by the National Institute of Allergy and Infectious Diseases under HHS contract HHSN27220140006C-OPT18I for the St Jude Center of Excellence for Influenza Research and Surveillance (P.G.T), JHCEIRS contract HHSN272201400007C, the National Institutes of Health R01AI084011 and R21HD095228 (A.G.R.), the National Institutes of Health and the National Natural Science Foundation of China under NIH-NSFC joint project 5R01AI128805-02, the National Natural Science Foundation of China under 81761128014, and ALSAC. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ASJC Scopus subject areas
- General
