Characterization of transcriptome dynamics in response to contact with host cells

Candida albicans is the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections which are often life threatening. Hematogenously disseminated candidiasis (HDC) has a 47% mortality rate despite current antifungal therapy. An increase in prevalence, as well as an increasing resistance to most of the clinically important antifungal therapies, provides a strong impetus to understand the molecular mechanisms of pathogenesis and the acquisition of drug resistance. This information holds promise to identify novel therapeutic targets. A complete and accurate characterization of how the transcriptome of C. albicans responds to its interaction with cells from the host is an absolute necessity to accomplish this goal. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to define comprehensively and systematically the transcriptome of an organism. We propose a comprehensive characterization of the C. albicans transcriptome in two different human tissue culture models, using RNA-seq. Such a characterization will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. A major problem in the design of antifungal agents stems from the fact that fungi and mammals are both eukaryotic organisms. Pharmaceutical compounds that can kill fungal cells will often kill human cells resulting in a drug having toxic side effects. Since a successful antifungal drug must inhibit the function of a gene that is expressed during the course of an infection, this work will provide a list of potential novel therapeutic targets to treat candidiasis, as well as mycoses caused by other serious invasive fungal pathogens, in the clinic. This project is led by Vincent M. Bruno, Ph.D., Institute for Genome Sciences, in collaboration with Dr. Scott Filler, David Geffen School of Medicine at UCLA.