P493 Functional genomics in Candida glabrata, new tools to study stress, pathogenesis and drug resistance

Abstract

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PMThe processes of life are dynamic and changes on a molecular level enable organisms to grow but to adapt 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 illnesses in humans ranging from allergic reactions, infections such as thrush which affects ∼75% of women at least once, to serious diseases 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. 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, 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 defenses. This suggests that resistance to both antifungal drugs and natural host-induced stresses are essential for the 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 to identify the critical genes involved in stress resistance and characterize the mechanisms of C. glabrata stress responses. My preliminary data demonstrate that the C. glabrata response to in vitro combinatorial stress is similar to that observed upon phagocyte engulfment. At the level of gene expression, there is an up-regulation of genes 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.