Prevalence and Mechanisms of Mucus Accumulation in COVID-19 Lung Disease

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  • Kato, Takafumi
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Asakura, Takanori
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Edwards, Caitlin E
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Dang, Hong
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Mikami, Yu
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Okuda, Kenichi
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Chen, Gang
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Sun, Ling
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Gilmore, Rodney C
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Hawkins, Padraig
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • De la Cruz, Gabriela
    • Affiliation: N.C. Cancer Hospital, UNC Lineberger Comprehensive Cancer Center
  • Cooley, Michelle R
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Bailey, Alexis B
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Hewitt, Stephen M
    • Other Affiliation: National Cancer Institute
  • Chertow, Daniel S.
    • Other Affiliation: NIH Clinical Center
  • NIH COVID-19 Autopsy Consortium
  • Borczuk, Alain C
    • Other Affiliation: Weill Cornell Medicine
  • Salvatore, Steven
    • Other Affiliation: Weill Cornell Medicine
  • Martinez, Fernando J.
    • Other Affiliation: Weill Cornell Medicine
  • Thorne, Leigh B
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Askin, Frederic B
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Ehre, Camille
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Randell, Scott H
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • O'Neal, Wanda K
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
  • Baric, Ralph S.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Boucher, Richard C
    • Affiliation: School of Medicine, Marsico Lung Institute/UNC Cystic Fibrosis Center
Abstract
  • Rationale: The incidence and sites of mucus accumulation, and molecular regulation of mucin gene expression, in COVID-19 lung disease have not been reported. Objectives: Characterize incidence of mucus accumulation and the mechanisms mediating mucin hypersecretion in COVID-19 lung disease. Methods: Airway mucus and mucins were evaluated in COVID-19 autopsy lungs by AB-PAS and immunohistochemical staining, RNA in situ hybridization, and spatial transcriptional profiling. SARS-CoV-2-infected human bronchial epithelial (HBE) cultures were utilized to investigate mechanisms of SARS-CoV-2-induced mucin expression and synthesis and test candidate countermeasures. Measurements and Main Results: MUC5B and variably MUC5AC RNA levels were increased throughout all airway regions of COVID-19 autopsy lungs, notably in the sub-acute/chronic disease phase following SARS-CoV-2 clearance. In the distal lung, MUC5B-dominated mucus plugging was observed in 90% of COVID-19 subjects in both morphologically identified bronchioles and microcysts, and MUC5B accumulated in damaged alveolar spaces. SARS-CoV-2-infected HBE cultures exhibited peak titers 3 days post inoculation, whereas induction of MUC5B/MUC5AC peaked 7-14 days post inoculation. SARS-CoV-2 infection of HBE cultures induced expression of EGFR ligands and inflammatory cytokines (e.g., IL-1α/β) associated with mucin gene regulation. Inhibiting EGFR/IL-1R pathways, or dexamethasone administration, reduced SARS-CoV-2-induced mucin expression. Conclusions: SARS-CoV-2 infection is associated with a high prevalence of distal airspace mucus accumulation and increased MUC5B expression in COVID-19 autopsy lungs. HBE culture studies identified roles for EGFR and IL-1R signaling in mucin gene regulation post SARS-CoV-2 infection. These data suggest that time-sensitive mucolytic agents, specific pathway inhibitors, or corticosteroid administration may be therapeutic for COVID-19 lung disease. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org.libproxy.lib.unc.edu/licenses/by-nc-nd/4.0/).
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  • Article
Rights statement
  • In Copyright
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  • Attribution-NonCommercial-NoDerivs 4.0 International
Journal title
  • American Journal of Respiratory and Critical Care Medicine
Language
  • English
Version
  • Postprint
ISSN
  • 1073-449X

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