Fungal nitrosative stress responses are understudied and poorly understood. Also, while the responses of the pathogen Candida albicans to individual oxidative and cationic stresses have been characterised relatively well, the responses of this pathogen to simultaneous combinations of these and nitrosative stresses have not been elaborated. Yet, C. albicans is exposed to these combinatorial stresses during disease progression. Therefore, the overall aim of this project was to characterise the "Nitrosative and Combinatorial Stress Responses in Candida albicans". The first objective was to elucidate nitrosative stress response mechanisms in C. albicans at a cellular, transcriptional and post-translational level. Genetic screens revealed that the Hog1 and Mkc1 signalling pathways contribute to nitrosative stress adaptation in addition to Cta4 signalling. The next objective was to characterise responses to combinatorial nitrosative, oxidative and/or cationic stresses with respect to the relevant signal transduction pathways. Unexpectedly, combinatorial stresses did not activate classical nitrosative (Cta4) and oxidative (Cap1) signalling mechanisms. Instead, Hog1 signalling was found to play a significant role in the combinatorial stress adaptation. Dramatic changes in the GSH redox potential were observed in response to both single and combinatorial stresses. Thus, GSH redox regulatory mechanisms were explored in more detail. BLAST searches of the C. albicans genome were performed, revealing genes encoding a putative NADPH-dependent glutathione reductase (Glr1) and a GSH-dependent S-nitrosoglutathione reductase (Fdh3). We confirmed that both conserved enzymes are involved in the maintenance of redox homeostasis and hence are crucial for C. albicans adaptation during host-pathogen interactions. This was achieved by showing that inactivation of Glr1 or Fdh3 disturbs GSH redox homeostasis, confers oxidative and formaldehyde stress sensitivity and attenuates virulence.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:569642 |
| Date | January 2013 |
| Creators | Tilliman, Anna Theresa |
| Publisher | University of Aberdeen |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=192303 |
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