Candida albicans, the major human fungal pathogen, is responsible for a wide variety of systemic and mucosal infections. AIDS patients, organ transplant recipients, cancer patients undergoing chemotherapy, recipients of artificial joints and prosthetic devices and other immunocompromised individuals are particularly susceptible to C. albicans infections. C. albicans is known to undergo a morphological transition from yeast (single, round budding cells) to pseudohyphal and hyphal filaments (elongated cells attached end-to-end) which is required for virulence. Our long-term goal is to determine how C. albicans controls morphology and promotes virulence in response to host environmental cues. Although phenotypic differences between pseudohyphal and hyphal forms have been well-characterized, very little is known about the regulatory mechanisms that determine growth in each morphology or the specific role that each morphology plays in virulence. In order to address these questions, we have recently generated a C. albicans strain that can be genetically manipulated to grow completely in the hyphal morphology under non-filament-inducing conditions in vitro. We have also found that this strain is capable of driving increased hyphal formation and promoting virulence in a mouse model of systemic candidiasis. Our strain was generated by placing one allele of a novel filament-specific transcriptional regulator of C. albicans hyphal extension and virulence, UME6, under the control of a regulatable promoter. Interestingly, while high-level UME6 expression drives complete hyphal growth, intermediate UME6 levels specify a largely pseudohyphal population, indicating that UME6 expression levels are sufficient to determine C. albicans morphology in a dosage-dependent manner. Preliminary studies show an increase in both the number of filament-specific transcripts induced as well as their level of induction as UME6 levels rise. Our hypothesis is that UME6 levels, which are affected by host environmental cues, determine C. albicans morphology and virulence by controlling the expression level of overlapping sets of filament-specific transcripts. In order to address this hypothesis we plan to carry out the following three specific aims: 1) determine how upstream host environmental signals and known C. albicans filamentous growth regulatory circuits control the expression of UME6, 2) determine the transcriptional profile of C. albicans genes expressed as UME6 dosage specifies pseudohyphal and hyphal morphologies and promotes virulence during infection, 3) identify specific downstream mechanisms that are important for the ability of UME6 levels to determine C. albicans morphology and promote virulence. Ultimately, these studies will significantly improve our understanding of how fungal pathogens specify morphology and promote virulence in the host environment and will provide information that could lead to the development of novel and more effective antifungal strategies.

Public Health Relevance

Candida albicans is the major yeast that causes yeast infections and also kills people with weakened immune systems. This research proposal aims to gain a better understanding of how Candida albicans is able to function as such an effective pathogen. Ultimately, these studies should provide information leading to the development of more effective treatments for yeast infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI083344-04
Application #
8463967
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Duncan, Rory A
Project Start
2010-05-15
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$362,599
Indirect Cost
$101,388
Name
University of Texas Health Science Center San Antonio
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Childers, Delma S; Mundodi, Vasanthakrishna; Banerjee, Mohua et al. (2014) A 5' UTR-mediated translational efficiency mechanism inhibits the Candida albicans morphological transition. Mol Microbiol 92:570-85
Banerjee, Mohua; Uppuluri, Priya; Zhao, Xiang R et al. (2013) Expression of UME6, a key regulator of Candida albicans hyphal development, enhances biofilm formation via Hgc1- and Sun41-dependent mechanisms. Eukaryot Cell 12:224-32
Carlisle, Patricia L; Kadosh, David (2013) A genome-wide transcriptional analysis of morphology determination in Candida albicans. Mol Biol Cell 24:246-60
Lackey, Erika; Vipulanandan, Geethanjali; Childers, Delma S et al. (2013) Comparative evolution of morphological regulatory functions in Candida species. Eukaryot Cell 12:1356-68
Kadosh, David; Lopez-Ribot, Jose L (2013) Candida albicans: adapting to succeed. Cell Host Microbe 14:483-5
Thompson, Delma S; Carlisle, Patricia L; Kadosh, David (2011) Coevolution of morphology and virulence in Candida species. Eukaryot Cell 10:1173-82
Carlisle, Patricia L; Kadosh, David (2010) Candida albicans Ume6, a filament-specific transcriptional regulator, directs hyphal growth via a pathway involving Hgc1 cyclin-related protein. Eukaryot Cell 9:1320-8