Cholinergic modulation of Candida albicans virulence factors and the pathogenesis of candidiasis

Alghamdi, Abeer Muhammad (2022) Cholinergic modulation of Candida albicans virulence factors and the pathogenesis of candidiasis. PhD thesis, University of Glasgow.

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Candida albicans is the most prevalent fungal pathogen causing both superficial and invasive fungal infections leading to various challenges on healthcare systems. Normally, C. albicans is a harmless commensal of the human body, but under certain conditions of stress, it can express virulence traits leading to disease. It causes a wide range of infections starting from superficial infections such as oropharyngeal candidiasis to systemic infections such as Candidemia. Biofilm formation is an important feature of C. albicans pathogenesis. There are several factors in C. albicans which contribute to this trait, such as morphological transition, expression of virulence factors, metabolic flexibility, and stress response machinery. Understanding the complexity of the pathways behind the virulence traits of C. albicans is essential for developing effective therapeutic strategies to combat superficial and life threatening systemic infections.

In this research, we present a novel antifungal activity of pilocarpine hydrochloride against C. albicans biofilms. We hypothesize that C. albicans may possess muscarinic like receptor(s) that mediate the ability of pilocarpine hydrochloride to inhibit biofilm formation. Pilocarpine hydrochloride reduced filamentation and biofilm formation significantly in a dose dependent manner in both the wild type strain and clinical isolates. The M5 allosteric modulator, similarly, inhibited the biofilm formation significantly in a dose dependent manner. Moreover, pilocarpine hydrochloride reduced the damage and inhibited the innate immune response stimulated by C. albicans infection in both TR146 cells and a three-dimensional human oral tissue model. The transcriptomic profile of C. albicans upon treatment with pilocarpine hydrochloride and acetylcholine revealed differential expression among crucial genes that play a vital role in C. albicans pathogenesis such as downregulation of hyphal specific genes; HWP1, ECE1, and IHD1. RNAseq data also revealed a considerable number of unannotated genes that may play a role in the cholinergic modulation of C. albicans biofilm formation by acetylcholine and pilocarpine hydrochloride.

The data generated herein suggest that C. albicans may possess a cholinergic receptor or receptors mediating C. albicans virulence factors. This research provides a foundation to explore further cholinergic pathways in fungal pathogens and their involvement in pathogenicity. It also reveals potential novel effective antifungal therapeutic targets in C. albicans. Furthermore, it emphasizes the feasibility and effectiveness of repurposing known licensed drugs, used for treatment of other conditions, to treat C. albicans infections singularly or as an adjunctive therapy. In the light of the global increased resistance to antifungal and antimicrobial therapies, this work may contribute to the development of more effective therapeutic strategies.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Supervisor's Name: Ramage, Professor Gordon and Riggio, Dr. Marcello
Date of Award: 2022
Depositing User: Theses Team
Unique ID: glathesis:2022-82916
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 31 May 2022 14:04
Last Modified: 31 May 2022 14:06
Thesis DOI: 10.5525/gla.thesis.82916
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