Antifungal Immune Responses and Inflammation in the Cystic Fibrosis Airways

Cystic Fibrosis (CF) is an inherited disease where the dysfunction of a single protein (the Cystic Fibrosis Transmembrane Regulator or CFTR), a chloride transporter found in both epithelial and immune cells, results in persistent infections and inflammation in the airways. It has been shown that Aspergillus fumigatus frequently infects the airways of people with CF and contributes to hyperinflammation and lung function decline. The studies presented in this thesis aimed to obtain an insight into the airway mycobiome of people with CF, as well as getting a broader understanding of the host-fungal interactions. This was done by assessing the immune and inflammatory responses to a range of fungal pathogens by immune cells and epithelial cells. My studies into the host-fungal interactions showed that the antifungal immune responses are fungus and fungal morphotype specific, and that the differences caused by the impaired function of the CFTR protein varies between host cell types. Aspergillus hyphae are more potent inducers of ROS than Aspergillus conidia, while Rasamsonia conidia are more potent inducers of ROS than Aspergillus conidia. No differences were observed in the antifungal responses between healthy and CF epithelial cells and neutrophils against Rasamsonia conidia. CF epithelial cells showed increased phagocytosis, but decreased killing, of Candida albicans blastospores. Interestingly, we observed that the previously described increase in Aspergillus-induced ROS production in CF neutrophils was no longer present in patients receiving treatment with the CFTR modulator Kaftrio. This strongly suggests that Kaftrio has an additional immunomodulating effect without compromising antifungal activity. I explored if FRISA (Fungal Ribosomal Intergenic Spacer Analysis) could be a valuable and easy to perform technique to study the mycobiome in clinical samples. Unfortunately, due to shortcomings inherent with the technique, I was unable to obtain meaningful results. As the CF antifungal immune responses are fungus and fungal morphotype specific and antifungal responses differ based on cell type and between healthy and CF cells, it is important to understand the composition of the mycobiome 3 within the CF airways to guide treatment. Especially during exacerbations, it is imperative to determine the best interventions to optimize clearance of the causative fungus and controlling the inflammation evoked. My results have shown that Kaftrio reduces the hyperinflammation against Aspergillus seen in the CF airways without effecting fungal clearance. And as a result of the widespread use of Kaftrio, and other CFTR modulators, the perspective of CF associated fungal disease may well be changing substantially.<p></p>

Author dc:creator

• Elliot Mahoney (21039332)

• Cystic Fibrosos
• Fungi
• Aspergillus

Statement dc:rights

• All rights reserved
• Open Access after 2027-08-16

Identifier

10779/exe.31348156.v1

OAI identifier oai:identifier

oai:figshare.com:article/31348156