Candida albicans switches spontaneously, reversibly and at high frequency between a limited number of general phenotypes distinguishable by colony morphology. Switching is highly pleiotropic, regulating a variety of phenotypic characteristics and involving the differential expression of phase-specific genes. Switching therefore, provides colonizing populations with spontaneous variants for rapid adaptation during commensalism and pathogenesis. Using the white-opaque phase transition in strain WO-1 as an experimental system, we have demonstrated that the histone deacetylase Hda1p functions as a suppressor of switching in the white-to-opaque direction, that the silent information regulatory Sir2p is not involved in the white-opaque transition, but functions as a suppressor of a second switching system analogous to that in strain 3153A, and that phase specific genes are regulated downstream of the switch event through phase-specific trans-acting factors. We now propose 1) to develop a more accurate model of the downstream regulatory circuitry involved in phase specific gene expression, 2) to elucidate the protein-DNA and protein-protein interactions involved in the regulation of select white and opaque phase genes, with emphasis on the role of the MADS box proteins in opaque phase expression of OP4, Rbf1p in white phase expression of WH11 and transcription of the phase regulated trans-acting factor EFG1, 3) to elucidate the roles of acetylation/deacetylation and gene silencing in switching, and 4) to assess the impact of the deletion of phase-specific regulatory molecules on pathogenesis in two animal models, one in which white phase cells are more pathogenic than opaque phase cells, and the other in which opaque phase cells are more pathogenic than white phase cells. The first three aims have been formulated so that they provide several independent starting points for a reverse genetic approach for elucidating switch loci and the switching mechanism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039735-07
Application #
6510497
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Duncan, Rory A
Project Start
1996-06-01
Project End
2006-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
7
Fiscal Year
2002
Total Cost
$257,250
Indirect Cost
Name
University of Iowa
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Bougnoux, Marie-Elisabeth; Pujol, Claude; Diogo, Dorothee et al. (2008) Mating is rare within as well as between clades of the human pathogen Candida albicans. Fungal Genet Biol 45:221-31
Pujol, Claude; Pfaller, Michael A; Soll, David R (2004) Flucytosine resistance is restricted to a single genetic clade of Candida albicans. Antimicrob Agents Chemother 48:262-6
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Zhao, Xiaomin; Pujol, Claude; Soll, David R et al. (2003) Allelic variation in the contiguous loci encoding Candida albicans ALS5, ALS1 and ALS9. Microbiology 149:2947-60
Joly, Sophie; Pujol, Claude; Soll, David R (2002) Microevolutionary changes and chromosomal translocations are more frequent at RPS loci in Candida dubliniensis than in Candida albicans. Infect Genet Evol 2:19-37
Soll, David R (2002) Candida commensalism and virulence: the evolution of phenotypic plasticity. Acta Trop 81:101-10
Enger, L; Joly, S; Pujol, C et al. (2001) Cloning and characterization of a complex DNA fingerprinting probe for Candida parapsilosis. J Clin Microbiol 39:658-69
Lachke, S A; Srikantha, T; Tsai, L K et al. (2000) Phenotypic switching in Candida glabrata involves phase-specific regulation of the metallothionein gene MT-II and the newly discovered hemolysin gene HLP. Infect Immun 68:884-95
Soll, D R (2000) The ins and outs of DNA fingerprinting the infectious fungi. Clin Microbiol Rev 13:332-70

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