Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19.

Autor: Narasimhan H; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA., Cheon IS; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Qian W; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Hu S; Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Parimon T; Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles CA 90048, USA., Li C; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Goplen N; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA., Wu Y; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Wei X; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Son YM; Department of Systems Biotechnology, Chung-Ang University, Anseong, Korea., Fink E; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Santos G; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Tang J; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Yao C; Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles CA 90048, USA., Muehling L; Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Canderan G; Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Kadl A; Division of Pulmonary and Critical Care Medicine, Department of medicine, University of Virginia, Charlottesville, VA 22908, USA., Cannon A; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Young S; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA., Hannan R; Division of Pulmonary and Critical Care Medicine, Department of medicine, University of Virginia, Charlottesville, VA 22908, USA., Bingham G; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA., Arish M; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Chaudhari AS; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Sturek J; Division of Pulmonary and Critical Care Medicine, Department of medicine, University of Virginia, Charlottesville, VA 22908, USA., Pramoonjago P; School of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Shim YM; Division of Pulmonary and Critical Care Medicine, Department of medicine, University of Virginia, Charlottesville, VA 22908, USA., Woodfolk J; Division of Asthma, Allergy and Immunology, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA., Zang C; Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA., Chen P; Women's Guild Lung Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles CA 90048, USA., Sun J; Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA.; Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA 22908, USA.; Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2023 Nov 28. Date of Electronic Publication: 2023 Nov 28.
DOI: 10.21203/rs.3.rs-3587418/v1
Abstrakt: The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8 + T cell-macrophage interactions in maintaining Krt8 hi transitional and ectopic Krt5 + basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8 + T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
Databáze: MEDLINE
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