Candida albicans is by far the most frequently isolated fungus from humans. It is a normal commensal of Man but is also capable of invading almost every site in the body and causing infections especially in an expanding population of immunocompromised hosts, including those infected with HIV. The organism is able to undergo reversible morphological transitions between unicellular yeast-like forms (blastospores) and filamentous forms (called hyphae or pseudohyphae depending on slight variations in the structure of the filament), in response to changes in the external environment, and this ability is considered pivotal to its pathogenic potential. However, this belief is based primarily upon the results obtained from a large number of virulence studies using C. albicans mutant strains unable to undergo this morphogenetic switch (i.e. delta-cph1, delta-efg1, delta-tup1, delta-nrg1): because all of these strains are locked in one or other form, definitive conclusions on the role of the morphogenetic conversion in virulence cannot be made. In a previous study, we engineered a conditional mutant strain in which a negative regulator (NRG1) of filamentation was placed under the control of a tetracycline regulatable promoter. Analysis of this strain revealed that these morphological transitions could be modified both in vitro and also within an animal (mouse) host during an infection. In this application, we propose to extend these studies to the only other known negative regulator of this process in C. albicans (RFG1) to more closely examine and further define the infectious process of this important fungal pathogen. This will be achieved first through the construction of a tet-RFG1 regulatable C. albicans strain, as we did for the NRG1 gene, then analyzing its behavior both in vitro and then during the course of an infection. In addition, we will perform genome wide transcriptional profiling to determine which C. albicans genes are negatively regulated by the Rfg1p protein and how these impact on virulence. 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. ? ? ?
| Yadev, Nishant P; Murdoch, Craig; Saville, Stephen P et al. (2011) Evaluation of tissue engineered models of the oral mucosa to investigate oral candidiasis. Microb Pathog 50:278-85 |
| Cleary, Ian A; Mulabagal, Priyadarshini; Reinhard, Sara M et al. (2010) Pseudohyphal regulation by the transcription factor Rfg1p in Candida albicans. Eukaryot Cell 9:1363-73 |
