Increased NFAT and NFκB signalling contribute to the hyperinflammatory phenotype in response to Aspergillus fumigatus in a mouse model of cystic fibrosis
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Aspergillus fumigatus (Af) is a major mould pathogen found ubiquitously in the air. It commonly infects the airways of people with cystic fibrosis (CF) leading to Aspergillus bronchitis or allergic bronchopulmonary aspergillosis. Resident alveolar macrophages and recruited neutrophils are important first lines of defence for clearance of Af in the lung. However, their contribution to the inflammatory phenotype in CF during Af infection is not well understood. Here, utilising CFTR deficient mice we describe a hyperinflammatory phenotype in both acute and allergic murine models of pulmonary aspergillosis. We show that during aspergillosis, CFTR deficiency leads to increased alveolar macrophage death and persistent inflammation of the airways in CF, accompanied by impaired fungal control. Utilising CFTR deficient murine cells and primary human CF cells we show that at a cellular level there is increased activation of NFκB and NFAT in response to Af which, as in in vivo models, is associated with increased cell death and reduced fungal control. Taken together, these studies indicate that CFTR deficiency promotes increased activation of inflammatory pathways, the induction of macrophage cell death and reduced fungal control contributing to the hyper-inflammatory of pulmonary aspergillosis phenotypes in CF.
Editor(s)
Fidel, Jr., Paul L
Date Issued
2025-02-04
Date Acceptance
2025-01-16
Citation
PLoS Pathogens, 2025, 21 (2)
ISSN
1553-7366
Publisher
Public Library of Science (PLoS)
Journal / Book Title
PLoS Pathogens
Volume
21
Issue
2
Copyright Statement
© 2025 Bercusson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/39903773
PII: PPATHOGENS-D-24-02512
Subjects
Animals
Aspergillus fumigatus
Cystic Fibrosis
Mice
NF-kappa B
Disease Models, Animal
Signal Transduction
Humans
Cystic Fibrosis Transmembrane Conductance Regulator
NFATC Transcription Factors
Phenotype
Inflammation
Macrophages, Alveolar
Mice, Knockout
Pulmonary Aspergillosis
Aspergillosis, Allergic Bronchopulmonary
Mice, Inbred C57BL
Publication Status
Published
Coverage Spatial
United States
Article Number
e1012784
Date Publish Online
2025-02-04