Molecular mechanisms of Aspergillosis: contribution and impact of inter- and intrastrain Aspergillus fumigatus variations on the influence of cyclic AMP expression in host airway epithelial cells

Smale, Lisa-Marie (2019) Molecular mechanisms of Aspergillosis: contribution and impact of inter- and intrastrain Aspergillus fumigatus variations on the influence of cyclic AMP expression in host airway epithelial cells. Master's Thesis / Essay, Pharmacy.

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Abstract

Aspergillus (A.) fumigatus relies on host immune status and comorbidities to cause a range of fungal syndromes, with Invasive Aspergillosis (IA) as a worst-case outcome due to mortality rates of 50-90%. Key features in IA include complex pathogen-host interactions, causing dysfunctional conidial internalisation in airway epithelial cells (AECs). Host cyclic adenosine monophosphate (cAMP) regulates similar autophagic pathways, and is often exploited by microbes. This thesis aims to clarify the participation of cAMP in the pathophysiology of IA via determining the effect of A. fumigatus, and its inter- and intrastrain variations, on cAMP production of AECs. Intracellular cAMP expression was measured in cell lysate via a competitive cAMP ELISA assay with 3-isobutyl-1-methylxanthine (IBMX) added to obtain sufficient baseline cAMP recovery. Resting conidia (RC), swollen conidia (SC) and ultraviolet (UV)-inactivated conidia of A. fumigatus B5233 and three clinical isolates (P1ms, P1ms and P2cs) were used to infect AECs. RC of all strains, at a multiplicity of infection (MOI) of 10, decreased cAMP production with an average of approximately 60%, but no differences were observed between effects of the clinical isolates. Intra-strain differences were found for B5233 and P2cs only, with RC being more potent than SC. This thesis suggests AEC cAMP signalling as a new potential target in IA, because it indicates that A. fumigatus conidia downregulate AEC cAMP. Furthermore, it indicates that fungal swelling coordinates this process, while interstrain differences only affect the dynamics of germination processes. Continued efforts need to make these pathways more accessible for development of treatment strategies.

Item Type:	Thesis (Master's Thesis / Essay)
Supervisor name:	Schmidt, M.
Degree programme:	Pharmacy
Thesis type:	Master's Thesis / Essay
Language:	English
Date Deposited:	26 Apr 2019
Last Modified:	30 Apr 2019 08:42
URI:	https://fse.studenttheses.ub.rug.nl/id/eprint/19396

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