Cystic fibrosis transmembrane conductance regulator regulates epithelial cell response to Aspergillus and resultant pulmonary inflammation

Neelkamal Chaudhary, Kausik Datta, Frederic B Askin, Janet F. Staab, Kieren Marr

Research output: Contribution to journalArticle

Abstract

Rationale: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) alter epithelial cell (EC) interactions with multiple microbes, such that dysregulated inflammation and injury occur with airway colonization in people with cystic fibrosis (CF). Aspergillus fumigatus frequently colonizes CF airways, but it has been assumed tobe an innocent saprophyte; its potential role as a cause of lung disease is controversial. Objectives: To study the interactions between Aspergillus and EC, and the role of the fungus in evoking inflammatory responses. Methods: A. fumigatus expressing green fluorescent protein was developed for in vitro and in vivo models, which used cell lines and mouse tracheal EC. Measurements and Main Results: Fungal spores (conidia) are rapidly ingested by ECs derived from bronchial cell lines and murine tracheas, supporting a role for EC in early airway clearance. Bronchial ECs harboring CFTR mutations (ΔF508) or deletion demonstrate impaired uptake and killing of conidia, and ECs with CFTR mutation undergo more conidial-induced apoptosis. Germinated (hyphal) forms of the fungus evoke secretion ofinflammatory mediators, with CFTR mutation resulting in increased airway levels of macrophage inflammatory protein 2 and KC, and higher lung monocyte chemotactic protein-1. After A. fumigatus inhalation, CFTR -/- mice develop exaggerated lymphocytic inflammation, mucin accumulation, and lung injury. Conclusions: Data demonstrate a critical role for CFTR in mediating EC responses to A. fumigatus. Results suggest that the fungus elicits aberrant pulmonary inflammation in the setting of CFTR mutation, supporting the potential role of antifungals to halt progressive CF lung disease.

Original languageEnglish (US)
Pages (from-to)301-310
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume185
Issue number3
DOIs
StatePublished - Feb 1 2012

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Cystic Fibrosis Transmembrane Conductance Regulator
Aspergillus
Pneumonia
Epithelial Cells
Aspergillus fumigatus
Fungal Spores
Mutation
Cystic Fibrosis
Fungi
Lung Diseases
Chemokine CXCL2
Inflammation
Cell Line
Chemokine CCL2
Lung Injury
Mucins
Green Fluorescent Proteins
Trachea
Cell Communication
Inhalation

Keywords

  • Aspergillus
  • Cystic fibrosis
  • Epithelial

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Cystic fibrosis transmembrane conductance regulator regulates epithelial cell response to Aspergillus and resultant pulmonary inflammation. / Chaudhary, Neelkamal; Datta, Kausik; Askin, Frederic B; Staab, Janet F.; Marr, Kieren.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 185, No. 3, 01.02.2012, p. 301-310.

Research output: Contribution to journalArticle

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