This application for a Competitive Revision to the previously funded project, R21DE019414-01 is in response to NOT-OD-09-058 """"""""NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications"""""""". Candida albicans causes both mucosal and disseminated disease. Oropharyngeal candidiasis (OPC) results in significant morbidity in many patients, especially those with HIV/AIDS. Hematogenously disseminated candidiasis (HDC) is a healthcare-associated disease that results in 30 to 50% mortality, even with current antifungal therapy. Although the clinical risk factors for development of OPC and HDC are well-defined, only a minority of patients who are at risk for either of these diseases actually develop them. An additional important determinant of susceptibility to OPC and HDC is the presence of polymorphisms in key genes that govern the host response to Candida albicans. The overall goal of this project is to use inbred strains of mice to identify these genes. This information holds promise to provide new insight into mechanisms of host defense against OPC and HDC, as well as to provide new genetic approaches to identify patients who are at particularly high risk of developing these diseases. We have already tested the susceptibility of 17 inbred mouse strains to OPC and HDC. We found that different strains had significantly different susceptibility to both diseases. Next, we used computational haplotype mapping to identify genomic regions--quantitative trait loci (QTLs)--that may contain genes whose variations are responsible for these strain-to-strain differences in disease susceptibility. The results of this analysis identified 78 and 176 genes in which polymorphisms may be associated with susceptibility to OPC and HDC, respectively. However, a limitation of haplotype mapping is that false positive results are frequent. Therefore additional methods are required to determine which of the genes in the QTLs actually influence susceptibility to these diseases. In this competitive revision, we propose to use microarray analysis to determine host gene expression levels in the oral tissues of different strains of mice that differ in their susceptibility to OPC. We plan to perform a similar analysis using RNA from the kidneys of different strains of mice that differ in susceptible to HDC (The kidney is the target organ in mice with HDC). These microarray data will be analyzed to determine which of the genes identified by haplotype mapping are: 1) expressed in the target organs, and 2) have different levels of expression in susceptible vs. resistant mouse strains. These data will enable us to prioritize disease susceptibility genes for further in-depth study. They will also be an excellent resource for understanding the host response to OPC and HDC, as well as for identifying potential biomarkers for these diseases.
This research is highly relevant to public health because oropharyngeal candidiasis is a significant problem in patients with HIV/AIDS, especially those who are not receiving highly active antiretroviral therapy. Also, hematogenously disseminated candidiasis is common in hospitalized patients and still causes significant mortality, even with treatment. Discovering host genes that govern susceptibility to oropharyngeal and disseminated candidiasis holds promise to provide new insight into mechanisms of host defense against these diseases, as well as to provide new genetic approaches to identify patients who are at particularly high risk of developing these diseases. In addition, this supplement will enable scientists and technicians at Los Angeles Biomedical Research Institute, Duke University, and Stanford University to devote significantly more time to this project, and thereby facilitate their continued full employment.
| Peltz, Gary; Zaas, Aimee K; Zheng, Ming et al. (2011) Next-generation computational genetic analysis: multiple complement alleles control survival after Candida albicans infection. Infect Immun 79:4472-9 |
