AC Cowley, A Horsley, DW Denning, DJ Thornton


The impact of fungal pathogens such as A. fumigatus on cystic fibrosis (CF) airways has until recently been underestimated. The use of more sensitive culture methods has begun to shed light on the prevalence of A. fumigatus in CF sputum, however its precise role in the progression of CF lung disease remains unclear. As the first point of contact for A. fumigatus following inhalation, the mucus barrier provides an important site for host-conidia interactions. Previous studies have suggested that A. fumigatus may alter the composition of the airway mucus barrier by altering mucin gene expression (1), and in the presence of mucin-based medium, A. fumigatus has been shown to upregulate protease expression and secretion (2). However, many aspects of this interplay are yet to be elucidated. Specifically, the effects of A. fumigatus on the major structural components of airway mucus, namely the polymeric gel-forming mucins (MUC5AC and MUC5B), have not been studied in detail. In order to investigate this further we studied the effects of A. fumigatus on the structural properties of purified solutions of MUC5AC and MUC5B, and on the physical properties of saliva: a model system of MUC5B-rich mucus.
The effects of A. fumigatus culture secretions on the size and glycosylation of purified mucins were studied. Micro-rheology studies were also performed to determine whether such changes may be reflected in the rheological properties of mucus. Furthermore, on-going experiments using air-liquid interface culture are studying the effects of A. fumigatus culture filtrates on mucin production and mucus gel properties in airway epithelial cells.
Our data suggest that A. fumigatus is able to degrade MUC5AC and MUC5B, by targeting both the protein and carbohydrate portions of the mucin molecules. Preliminary experiments suggest that proteolytic degradation of mucins is most likely mediated by serine protease activity. This degradation is reflected by an apparent loss in the viscosity of saliva following exposure to A. fumigatus secretions (3.35 MPa over 1 hour), suggesting that the structural organisation of the mucin network is being altered.
These effects may highlight important mechanisms of A. fumigatus pathogenesis, whereby it degrades mucins either as a nutrient source, or to physically diminish the mucus barrier in order to facilitate airway colonisation.


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7th Advances Against Aspergillosis Conference