Aspergillus fumigatus is a filamentous fungus and the main pathogen responsible for the often fatal respiratory condition, aspergillosis. Airway epithelial cells (AECs) are likely to be the first line of host defence that come into contact with the inhaled conidia of A. fumigatus. Recent evidence strongly suggests that the response of the airway epithelium to inhaled pathogens is pivotal in orchestrating immune responses by inducing phagocytic-like reactions and the secretion of inflammatory cytokines and antimicrobial peptides. However, the majority of previous work investigating A. fumigatus-host interactions has been performed using macrophages and neutrophils, thereby neglecting the epithelium. AECs have been shown to secrete inflammatory cytokines in response to A. fumigatus although these studies predominantly used transformed AEC lines that lack tight junctions and do not fully differentiate. Furthermore, most studies used culture filtrate or extract of A. fumigatus rather than live, whole organism and as a result, the direct interaction of the germinating fungus and the airway epithelium has been overlooked. During the early germination and growth period, the cell wall composition of A. fumigatus is dynamic, with various antigens exposed at different morphological stages. The aim of this thesis was to determine whether AECsare able to alter the germination and growth rate of A. fumigatus, and, conversely, if A. fumigatus affects AECs in terms of the secretion of inflammatory mediators. These studies used live, germinating A. fumigatus, and human primary differentiated AECs to obtain a more realistic in vitro model than those used in previous studies. Data showed that AECs are able to significantly inhibit the germination and growth of A. fumigatus, although this effect was less pronounced in differentiated primary AEC than in transformed AEC lines. A. fumigatus also significantly inducedthe expression and secretion of the inflammatory cytokines, IL-6 and IL-8, probably via the interaction of fungal cell wall β-glucans, and as of yet unidentified AEC receptor. The A1160pyrG+ strain of A. fumigatus secreted factors capable of inducing cytokine secretion whereas Af293 strain did not, highlighting diverse mechanisms of action for different strains. Upregulation of both cytokines was dependent on the stage of A. fumigatus growth with induction synchronous with germination. Despite being associated with fungal sensitisation in asthmatics, AEC-derived cytokines associated with this disease, namely TSLP, IL33 and IL25,did not appear to be upregulated by transformed AECs in response to A. fumigatus. Similarly, A. fumigatus did not seem to induce synthesis and secretion of the acute phase response protein, fibrinogen above baseline levels. The data presented in this thesis confirms the importance of the airway epithelium in directing anti-A. fumigatus immunity and the involvement of complex ligand-receptor interactions.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:617993 |
| Date | January 2014 |
| Creators | Rowley, Jessica |
| Contributors | Herrick, Sarah; Richardson, Malcolm |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/the-interaction-of-aspergillus-fumigatus-with-the-respiratory-epithelium(0fc10449-977d-4f14-a169-172e8204fee4).html |
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