Differential proinflammatory responses to Aspergillus fumigatus by airway epithelial cells in vitro are protease dependent

Rowley, J; Namvar, S; Gago, S; Labram, B; Bowyer, P; Richardson, MD; Herrick, SE

Abstract

Aspergillus fumigatus is an important human respiratory mould pathogen. In addition to a barrier function, airway epithelium elicits a robust defence against inhaled A. fumigatus by initiating an immune response. The manner by which A. fumigatus initiates this response and the reasons for the immunological heterogeneity with different isolates are unclear. Both direct fungal cell wall–epithelial cell interaction and secretion of soluble proteases have been proposed as possible mechanisms. Our aim was to determine the contribution of fungal proteases to the induction of epithelial IL-6 and IL-8 in response to different A. fumigatus isolates. Airway epithelial cells were exposed to conidia from a low or high protease-producing strain of A. fumigatus, and IL-6 and IL-8 gene expression and protein production were quantified. The role of proteases in cytokine production was further determined using specific protease inhibitors. The proinflammatory cytokine response correlated with conidia germination and hyphal extension. IL-8 induction was significantly reduced in the presence of matrix metalloprotease or cysteine protease inhibitors. With a high protease-producing strain of A. fumigatus, IL-6 release was metalloprotease dependent. Dectin-1 antagonism also inhibited the production of both cytokines. In conclusion, A. fumigatus-secreted proteases mediate a proinflammatory response by airway epithelial cells in a strain-dependent manner.

Citation

Rowley, J., Namvar, S., Gago, S., Labram, B., Bowyer, P., Richardson, M., & Herrick, S. (2021). Differential proinflammatory responses to Aspergillus fumigatus by airway epithelial cells in vitro are protease dependent. Journal of Fungi, 7(6), e468. https://doi.org/10.3390/jof7060468

• Journal Article Type: Article
• Acceptance Date: Jun 3, 2021
• Publication Date: Jun 10, 2021
• Deposit Date: Jun 14, 2021
• Publicly Available Date: Jun 14, 2021
• Journal: Journal of Fungi
• Print ISSN: 2309-608X
• Publisher: MDPI
• Volume: 7
• Issue: 6
• Pages: e468
• DOI: https://doi.org/10.3390/jof7060468
• Publisher URL: https://doi.org/10.3390/jof7060468
• Related Public URLs: https://www.mdpi.com/journal/jof
• Additional Information: Additional Information : Jessica Rowley and Sara Namvar are joint first authors of this work and contributed equally to it.; Funders : Fungal Infection Trust;National Aspergillosis Centre;University Hospital of South Manchester NHS Foundation Trust;Medical Research Council (MRC)