Candida albicans is the most often cited agent of opportunitistic fungal infections. The incidence of candidal infections have increased substantially over the past decade and concerns over this trend are heightened by the lack of efficacious treatments and high mortality rates. Despite a voluminous literature on C. Albicans, dealing largely with diagnostic techniques and research into its pathogenicity, much of its biology remains hidden. The mechanism(s) of pathogenesis continues to be a topic of conjecture and debate, however, the dimorphic ability of C. Albicans is regarded a significant contributing factor. The investigator previously identified several candidal genes differentially expressed in relation to the dimorphic response. One of these genes, PHR1, is transcriptionally regulated in responses to ambient pH, an environmental signal known to modulate the dimorphic transition of C. Albicans. A second pH-regulated gene, PHR2, encodes a structural and functional homolog of PHR1. Genetic studies have demonstrated that both are required for morphogenesis and virulence and probably encode an essential cell function. Preliminary studies suggest that these genes encode a glycosidase/glycosyl transferase activity that participates in cell wall assembly. While this function is not specific to hypase, the investigator has found a hyphal-specific gene that is dependent upon PHR1 expression. This indicates that the progression of morphogenesis is monitored by the cell and that for some hyphal-specific genes, expression is directly linked to morphogenesis. The investigator has proposed a series of biochemical and genetic experiments to further define the structure and function of the proteins encoded by PHR1 and PHR2 and to define the molecular mechanism(s) that integrate morphogenesis with hyphal-specific gene expression. This information will provide fundamental insights into the process of candidal morphogenesis and will contribute to the investigators long term objective of understanding the molecular basis of dimorphism and its role in pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM047727-06
Application #
2685001
Study Section
Special Emphasis Panel (ZRG5-BM-2 (03))
Project Start
1992-05-01
Project End
2001-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
6
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Georgetown University
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
McNemar, Mark D; Fonzi, William A (2002) Conserved serine/threonine kinase encoded by CBK1 regulates expression of several hypha-associated transcripts and genes encoding cell wall proteins in Candida albicans. J Bacteriol 184:2058-61
Fonzi, W A (2002) Role of pH response in Candida albicans virulence. Mycoses 45 Suppl 1:16-21
Porta, A; Wang, Z; Ramon, A et al. (2001) Spontaneous second-site suppressors of the filamentation defect of prr1Delta mutants define a critical domain of Rim101p in Candida albicans. Mol Genet Genomics 266:624-31
El Barkani, A; Kurzai, O; Fonzi, W A et al. (2000) Dominant active alleles of RIM101 (PRR2) bypass the pH restriction on filamentation of Candida albicans. Mol Cell Biol 20:4635-47
Yesland, K; Fonzi, W A (2000) Allele-specific gene targeting in Candida albicans results from heterology between alleles. Microbiology 146 ( Pt 9):2097-104
Porta, A; Ramon, A M; Fonzi, W A (1999) PRR1, a homolog of Aspergillus nidulans palF, controls pH-dependent gene expression and filamentation in Candida albicans. J Bacteriol 181:7516-23
Sharkey, L L; McNemar, M D; Saporito-Irwin, S M et al. (1999) HWP1 functions in the morphological development of Candida albicans downstream of EFG1, TUP1, and RBF1. J Bacteriol 181:5273-9
Ramon, A M; Porta, A; Fonzi, W A (1999) Effect of environmental pH on morphological development of Candida albicans is mediated via the PacC-related transcription factor encoded by PRR2. J Bacteriol 181:7524-30
Fonzi, W A (1999) PHR1 and PHR2 of Candida albicans encode putative glycosidases required for proper cross-linking of beta-1,3- and beta-1,6-glucans. J Bacteriol 181:7070-9
De Bernardis, F; Muhlschlegel, F A; Cassone, A et al. (1998) The pH of the host niche controls gene expression in and virulence of Candida albicans. Infect Immun 66:3317-25

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