Candida albicans is an opportunistic pathogen that causes oropharyngeal disease in a large and diverse population of patients, including those with HIV/AIDS. Azole antifungal agents are the current mainstay of therapy for oropharyngeal candidiasis. However, because of the emergence of azole resistance, it is critical to develop novel strategies to prevent and treat this disease. Our goal is to identify new C. albicans virulence genes and to determine the mechanisms by which they contribute to pathogenicity. This information holds Dromise to identify new targets for antifungal strategies. During an oropharyngeal infection, C. albicans invades and damages oral epithelial cells. We have found that many C. albicans mutants with decreased virulence in the mouse model of oropharyngeal candidiasis also have reduced ability to invade and damage oral epithelial cells in vitro. Therefore, we hypothesize that the capacity of C. albicans to invade and damage oral epithelial cells is critical for the organism to establish and maintain an oropharyngeal infection. Our objective is to use in vitro studies of the interactions between C. albicans and oral epithelial cells to define mechanisms of host-pathogen interaction. Specifically, we will determine the mechanisms by which C. albicans invades and injures oral epithelial cells through the following aims. (1) We will identify the epithelial cell receptors that C. albicans uses to invade this host cell. (2) We will use our existing information on the transcriptional response of C. albicans to oral epithelial cells to identify C. albicans genes encoding potential virulence factors that are necessary for oral epithelial cell damage. The function of these genes will be investigated by constructing insertion and overexpression mutants. These mutants will be screened for their ability to damage epithelial cells in vitro. (3) Mutants with epithelial cell damage defects will be analyzed further by determining the epithelial cell receptors to which they bind, their ability to invade oral epithelial cells in vitro, and their virulence in the mouse model of oropharyngeal candidiasis. (4) The functional relationships among C. albicans virulence genes will be elucidated by transcriptional profiling and epistasis analysis using both newly created and existing C. albicans mutants. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE017088-03
Application #
7232034
Study Section
Special Emphasis Panel (ZRG1-AARR-A (04))
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
2005-08-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$327,367
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
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Gil-Bona, Ana; Parra-Giraldo, Claudia Marcela; Hernáez, María Luisa et al. (2015) Candida albicans cell shaving uncovers new proteins involved in cell wall integrity, yeast to hypha transition, stress response and host-pathogen interaction. J Proteomics 127:340-351

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