Voelcker Academy

Research Symposium 2010

 

previous next
 
Cecille Sorio

Role of Candida albicans FDH1 in Promoting Virulence and Survival in the Host

Cecille Sorio

Mentor: David Kadosh

The ability of Candida albicans, the major human fungal pathogen, to transition from yeast to pseudohyphal and hyphal filaments is essential for virulence. Hyphal filaments play a role in several virulence-related properties, including the ability to lyse macrophages and neutrophils (essential for the host immune response). We have recently identified a transcriptional regulator, Ume6, which is specifically induced in response to filament-inducing conditions. ume6D/D mutants are defective for extension of hyphal filaments and attenuated for virulence in a mouse model of systemic candidiasis. Strikingly, we have found that constitutive high-level expression of UME6 is sufficient to drive nearly complete hyphal formation even in the absence of filament-inducing conditions in vitro. During a systemic mouse infection constitutive UME6 expression also caused increased virulence, tissue invasion, hyphal formation and hyphal extension. In order to identify genes responsible for the ability of Ume6 to promote virulence and hyphal extension we performed a DNA microarray analysis. This analysis has identified 216 C. albicans genes which are up-regulated > 2-fold as high levels of Ume6 direct hyphal formation under non-filament-inducing conditions. This gene set included several known and putative C. albicans virulence factors. One of the most highly induced genes was formate dehydrogenase, FDH1. FDH1 encodes an enzyme responsible for the oxidation of formate, a toxic by-product of the glyoxylate cycle. The glyoxylate cycle is an alternative carbon utilization pathway which is activated in C. albicans upon phagocytosis by macrophages. More specifically, the host cell starves C. albicans of glucose and this pathway allows C. albicans to survive and filament in the macrophage by using simple 2-carbon compounds generated by b-oxidation of fatty acids for energy production. Our hypothesis is that by oxidizing a toxic by-product of the glyoxylate cycle, Fdh1 plays an important role in promoting virulence and allowing C. albicans to survive and eventually lyse macrophages. We are planning to use a variety of genetic and molecular biological approaches to address this hypothesis, including the generation of FDH1 homozygous deletion and overexpression strains as well as transcript analysis.