Differential Proinflammatory Responses to Aspergillus fumigatus by Airway Epithelial Cells In Vitro Are Protease
Jessica Rowley1, Sara Namvar1,2, Sara Gago1,3,4
1School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester and Manchester Academic Health Science Centre, Manchester M13 9PT, UK.
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.
Insights
Fungal proteases from Aspergillus fumigatus trigger airway epithelial immune responses, with higher protease production leading to increased inflammation. Inhibiting these proteases reduces cytokine release, highlighting their role in respiratory infections.
Area of Science:
- Immunology
- Microbiology
- Pulmonary Medicine
Background:
- Aspergillus fumigatus is a significant human respiratory pathogen.
- Airway epithelium mounts a defense against A. fumigatus through immune responses.
- Mechanisms initiating these responses and isolate-specific variations are not fully understood.
Purpose of the Study:
- To investigate the role of fungal proteases in inducing epithelial interleukin-6 (IL-6) and IL-8.
- To determine if protease contribution varies between different A. fumigatus isolates.
Main Methods:
- Exposure of airway epithelial cells to low and high protease-producing A. fumigatus strains.
- Quantification of IL-6 and IL-8 gene expression and protein production.
- Use of specific protease inhibitors and Dectin-1 antagonism to assess protease function.
Main Results:
- Proinflammatory cytokine response correlated with fungal germination and hyphal growth.
- Matrix metalloprotease and cysteine protease inhibitors significantly reduced IL-8 induction.
- IL-6 release was dependent on metalloproteases with high protease-producing strains.
- Dectin-1 antagonism inhibited the production of both cytokines.
Conclusions:
- Aspergillus fumigatus-secreted proteases mediate proinflammatory responses in airway epithelial cells.
- The protease contribution to immune activation is strain-dependent.
- Fungal proteases are key mediators in the host-pathogen interaction during respiratory infections.
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