Candida albicans is the most common etiological agent of candidiasis, now the fourth leading cause of nosocomial infections. Even with aggressive drug therapy the prognosis for the patient is not good with mortality rates ranging from 30-50%, not to mention the significant economic burden associated with treatment. C. albicans is able to undergo reversible morphological transitions between unicellular yeast-like and filamentous forms and it is this attribute that is considered pivotal to its pathogenic potential. However, the current understanding of the role played by morphogenesis in C. albicans virulence is based primarily on data obtained from studies using genetically defined mutant strains unable to undergo this developmental programme. To overcome these concerns, we have constructed a tet-NRG1 regulatable strain (SSY50-B) in which morphogenetic conversions can be externally manipulated both in vitro and in vivo. Virulence studies performed using this strain have provided the most compelling evidence to date linking morphogenesis and virulence in this opportunistic pathogen. This application aims to further explore the mechanisms by which NRG1 regulates C. albicans filamentation and virulence for which we propose three specific aims: i) to use a genetic screen to identify NRG1-regulated genes that play key roles in C. albicans filamentation and pathogenesis, ii) to assess the individual roles of the NRG1-regulated genes in virulence by constructing """"""""knock out"""""""" mutant strains and testing them in a murine model of disseminated candidiasis and iii) to screen small molecule libraries to identify compounds that inhibit filamentation and virulence by mimicking C. albicans Nrglp function. ? ? Relevance to public health: Candida albicans is the main causative agent of candidiasis, the most frequent fungal infection and now the fourth leading cause of infections in US hospitals, with high mortality rates and soaring economic burden. The main idea behind this study is to further investigate the relationship between filamentation and virulence, as controlled by key regulatory genes, which may serve as the basis for the development of novel strategies for the treatment of these infections. ? ? ?
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