Oropharyngeal candidiasis (OPC) is among the first clinical manifestations of AIDS. It occurs in 50-95% of HIV+ individuals during the progression to AIDS, and overall prevalence among AIDS patients is estimated by the CDC at 9-31%. This infection is caused primarily by Candida albicans, a commensal fungus that can cause mucosal and invasive infections. Our overall objective is to understand the C. albicans gene products that govern host interaction and contribute to pathogenesis of OPC. We will use a new gene expression assay technology, nanoString nCounter RNA measurements, to determine levels of C. albicans gene expression during infection in widely used a murine OPC model. Our preliminary results correlate well with prior patient sample and in vitro infection gene expression data, but also reveal extensive stress-responsive gene expression and rewiring of transcription factor-target gene relationships. Proposed studies focus on two classes of gene products: transcription factors, and surface and secreted proteins. We have chosen transcription factor genes because they are a highly regulated gene set, and their products have been or can be connected to functions through systematic mutant screens, expression profiling, and chromatin immunoprecipitation. We have chosen surface and secreted protein genes because their products are engaged in direct interaction with host cells, and because they present the most accessible therapeutic targets. We will develop a reference dataset that explores expression of these genes, and extend the analysis with functional validation. Our findings will generate new hypotheses and inform choices of genes and pathways that can be pursued by all investigators in the community. Statement of Public Health Relevance: Our studies focus on oropharyngeal candidiasis, an infection for which AIDS patients are at risk. Our approach will identify high-priority therapeutic targets expressed by the pathogen that causes this infection. The results will guide drug development and will help to focus basic research studies on gene products that are directly relevant to this disease.

Public Health Relevance

Our studies focus on oropharyngeal candidiasis, an infection for which AIDS patients are at risk. Our approach will identify high-priority therapeutic targets expressed by the pathogen that causes this infection. The results will guide drug development and will help to focus basic research studies on gene products that are directly relevant to this disease. PUBLIC HEALTH RELEVANCE: Candida albicans is the major causative agent of oropharyngeal candidiasis, an infection that affects almost all AIDS patients. Our goal is to define the genes that are expressed by C. albicans during oropharyngeal candidiasis. Gene products thus identified will be key targets for therapeutic development.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DE023311-02
Application #
8633034
Study Section
AIDS-associated Opportunistic Infections and Cancer Study Section (AOIC)
Program Officer
Rodriguez-Chavez, Isaac R
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Carnegie-Mellon University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Liu, Yaoping; Solis, Norma V; Heilmann, Clemens J et al. (2014) Role of retrograde trafficking in stress response, host cell interactions, and virulence of Candida albicans. Eukaryot Cell 13:279-87