Combatting resistance to combinatorial stress and macrophage killing in Candida glabrata.

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The processes of life are dynamic and it is change on a molecular level that enables organisms to grow but to also adapt to and survive in different environments, such as the ability to cause disease within a human host. My research focuses on the human fungal pathogen, Candida glabrata, which can cause illness in humans ranging from allergic reactions, infections such as thrush which affects ~75% of women at least once, to serious disease in patients that have impaired immune systems. These fungi are increasing in incidence and the reason for this increase is not understood. However, it is clear that the fungus can defend itself against high levels of stress and antifungal drugs used in treatment regimes. My hypothesis is that C. glabrata has evolved the capabilities to withstand a challenge from the combination of environmental and imposed drug stresses.Firstly, to look at C. glabrata, I will take advantage of my recent discovery of the sexual cycle in this fungus which offers novel methods to test hypotheses about evolution and pathogenesis. Pathogens of humans (microbes that can cause infection), such as C. glabrata, are successful because they adapt effectively to environmental stresses encountered within the host body. Upon recognition by host immune cells, C. glabrata is engulfed and exposed to a combination of stresses. In contrast to other pathogenic fungi, C. glabrata is highly resistant to stress allowing it to survive the host immune defences. This suggests that resistance to both antifungal drugs (a stress brought on by medical intervention) and natural host-induced stresses are essential for establishment and progression of infection. The molecular mechanisms underpinning antifungal resistance and the response to individual stresses, have been investigated in isolation, however little is known about how C. glabrata adapts to combinatorial stresses. The mechanistic explanation of stress adaptation will yield new insights into Candida infection. Using my newly discovered sexual cycle in C. glabrata, I have generated a series of related strains of the same fungal pathogen that have increased resistance to combinatorial and drug stresses. I will sequence their genomes (a process for analysing DNA) to identify the critical genes involved in stress resistance and characterise the mechanisms of C. glabrata stress responses. My preliminary data and publications demonstrate that the C. glabrata response to in vitro (performed in the lab outside of the human body) combinatorial stress is similar to that observed upon phagocyte engulfment (when immune cells recognise pathogens and try to remove them). At the level of gene expression, there is an up-regulation of genes (the process by which information encoded in a gene is used to make more proteins) encoding functions related to stress adaptation and nutrient recycling overlap. Understanding this regulatory network and the role that selected components (different genes) play in stress resistance, is essential to the development of future drug regimes.