Biosciences Research Seminar - Combatting resistance to combinatorial stress and macrophage killing in Candida glabrata

Candida species are the fourth most commonly isolated pathogens from bloodstream infections. Infection is currently very difficult to diagnose and even with best practice, mortality rates approach 50%. Although Candida albicans is the main causative agent, the incidence of Candida glabrata infection has grown rapidly and is now responsible for ~25% of cases. The reason for this increasing incidence of C. glabrata infection is not fully understood, but it is clear that it has a higher tolerance to stress conditions. One reason pathogens of humans such as Candida glabrata are successful is their ability to adapt to environmental stresses encountered within the host. Upon recognition by host immune cells, C. glabrata is engulfed and exposed to a combination of oxidative and cationic stress, (combinatorial stress). However, in contrast to other pathogenic fungi, C. glabrata is highly resistant to this combinatorial stress, allowing it to survive the host innate immune defences. This suggests that resistance to both antifungal drugs (a clinically imparted stress) and host-induced combinatorial stress are essential for the establishment and progression of C. glabrata infection. The molecular mechanisms underpinning azole resistance, and the response to individual stresses, are relatively established little is known regarding how C. glabrata adapts to combinatorial stress.

I am working to characterize the gene regulatory network underpinning C. glabrata adaptation to combinatorial stress and azole drug resistance. My pilot data demonstrates that the C. glabrata response to in vitro combinatorial stress is very similar to that observed upon phagocyte engulfment, both at the level of gene expression, where up-regulation of genes encoding functions related to stress adaptation and nutrient recycling overlap. Understanding this network, and the role that selected components play in combinatorial stress resistance, is essential to the long-term development of small molecule inhibitors. The overarching goal of this work is to identify novel therapeutic targets within the C. glabrata combinatorial stress and azole resistance networks and begin their functional characterization.