Analysis of Candida albicans NRG1-regulated gene expression in vivo.

University Of Texas San Antonio, San Antonio TX

Investigators

Abstract

[unreadable] DESCRIPTION (provided by applicant): 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 particularly in HIV infected or otherwise immunocompromised hosts. 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 (i.e. ?cphl, ?efgl, ?tupl, ?nrgl) unable to undergo this morphogenetic switch: because all of these strains are locked in one or other form, definitive conclusions on the role of these morphogenetic changes in virulence cannot be made. To address these concerns, 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 has revealed that morphological transitions and, perhaps more importantly, the virulence of the organism can be modified during an infection within an animal host by simply altering the amount of NRG1 being expressed in the fungus: Nrg1 p, however, is known to be a global repressor protein responsible for the suppression of numerous C. albicans genes not all of which are involved in the process of filamentation. The aim of this proposal therefore is to examine how the C. albicans global expression profile is altered by NRG1 overexpression by performing microarray analysis of fungal cells isolated directly from infected animal tissues. 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. [unreadable] [unreadable] [unreadable]