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

Am J Respir Crit Care Med. 2012 Feb 1;185(3):301-10. doi: 10.1164/rccm.201106-1027OC. Epub 2011 Dec 1.


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 to be 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 of inflammatory 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Aspergillosis / metabolism*
  • Aspergillus fumigatus / physiology*
  • Bronchi / metabolism
  • Bronchi / microbiology
  • Cell Line
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator / deficiency
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Cytokines / metabolism
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Epithelial Cells / microbiology*
  • Flow Cytometry
  • Host-Pathogen Interactions*
  • Immunity, Cellular
  • Inflammation / etiology
  • Lung / immunology
  • Lung / metabolism
  • Lung / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Respiratory Mucosa / metabolism
  • Respiratory Mucosa / microbiology*
  • Trachea / metabolism
  • Trachea / microbiology


  • Cytokines
  • Cystic Fibrosis Transmembrane Conductance Regulator