An interwoven transcriptional network controls chlamydospore formation in the human fungal pathogen Candida albicans
The primary project of my dissertation focused on studying the regulation of chlamydospores, a morphology formed by the common human fungal pathogen Candida albicans. C. albicans produces chlamydospores under stressful conditions, however, the biological functions of chlamydospores are still unknown. Since this important human fungal pathogen produces these enigmatic structures, I believe that chlamydospores must provide a selective advantage to C. albicans. I hypothesized that there must be underlying developmental and regulatory pathways dedicated to chlamydospore formation, and that identifying these pathways will be useful in understanding the biological functions of chlamydospores. Using forward genetics and genome-wide approaches including RNA-seq and ChIP-seq, I discovered that the C. albicans chlamydospore transcriptional regulatory network is highly interwoven comprised of nine core transcriptional regulators (i.e., transcription factors) controlling over 3,200 downstream target genes. Of these nine core regulators, I have found that six core transcription factor deletion mutant strains fail to form chlamydospores, while three core transcription factor deletion mutant strains form higher numbers of chlamydospores relative to the wildtype strain. Analysis of the chlamydospore regulatory network suggests roles for SNARE vesicular transport and fatty acid degradation pathways along with roles for enzymes involved in cell wall biosynthesis pathways. Preliminary network conservation analyses based on orthologous relationships of proteins within the chlamydospore network revealed that the network is comprised largely of “old” proteins (65%) interspersed with some “young” proteins (35%), indicative of the network being fairly well conserved. Further analysis of this regulatory network will be useful in identifying the biological functions of chlamydospores and will also give us insight into the regulation of C. albicans morphological transitions more generally. Another project of my dissertation focused on studying non-drug therapeutic strategies to target biofilm formation in C. albicans and Candida auris. C. albicans and C. auris form robust and drug resistant biofilms and treatment of biofilm infections caused by these species is challenging. I focused on exploring red, green and blue visible lights in combination with exogenous photosensitizing compounds as a non-drug therapeutic strategy against C. albicans and C. auris biofilm in vitro. I demonstrated that red, green and blue visible lights in combination with exogenous photosensitizing compounds are an effective non-drug therapeutic strategy against both Candida species biofilms. Blue light with and without photosensitizing compounds was the most effective treatment at inhibiting biofilm formation and also disrupting mature biofilms of both species, closely followed by red light in combination with photosensitizing compounds.