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CFTR Modulators Dampen Aspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes

Alexander J Currie1,2, Ellen T Main1, Heather M Wilson1

  • 1Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.

Frontiers in Cellular and Infection Microbiology
|August 15, 2020
PubMed

Insights

Current cystic fibrosis (CF) therapies, specifically CFTR modulators, reduce Aspergillus-induced inflammation by decreasing reactive oxygen species (ROS) in immune cells. However, these treatments do not directly kill Aspergillus or enhance antifungal activity.

Area of Science:

  • Immunology
  • Infectious Diseases
  • Respiratory Medicine

Background:

  • Excessive inflammation during Aspergillus fumigatus infection contributes to lung function decline in cystic fibrosis (CF) patients.
  • CFTR modulators can reduce A. fumigatus colonization, but their anti-inflammatory and antifungal mechanisms remain unclear.
  • Other CF therapies like azithromycin and acebilustat may possess immunomodulatory properties against Aspergillus-induced inflammation.

Purpose of the Study:

  • To investigate the effects of CFTR modulators, azithromycin, and acebilustat on reactive oxygen species (ROS) production and fungal killing in immune cells from CF patients challenged with A. fumigatus.
  • To determine if these therapies enhance direct or indirect antifungal immune mechanisms.

Main Methods:

  • Peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) were isolated from CF patients and healthy volunteers.
  • Cells were pre-treated with CFTR modulators (ivacaftor/lumacaftor), azithromycin, or acebilustat before challenge with A. fumigatus.
  • ROS production and antifungal activity (direct/indirect) were measured.

Main Results:

  • Ivacaftor/lumacaftor significantly reduced Aspergillus-induced ROS production in PMNs from both CF patients and control subjects.
  • Ivacaftor alone or combined with lumacaftor significantly reduced ROS in CF and control PBMCs.
  • Azithromycin and acebilustat had no significant effect on ROS production; none of the tested treatments demonstrated direct or indirect antifungal activity.

Conclusions:

  • CFTR modulators exhibit potential immunomodulatory benefits by reducing Aspergillus-induced inflammation in CF patients through decreased ROS production.
  • The observed effects in healthy control subjects suggest mechanisms beyond direct CFTR modulation, warranting further investigation.
  • Current CF therapies do not directly eliminate Aspergillus or enhance immune-mediated fungal clearance.
Keywords:
Aspergillus fumigatusCFTR modulatorsacebilustatazithromycincystic fibrosisinflammationphagocytes

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