Genetics of susceptibility to candidiasis

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DESCRIPTION (provided by applicant): 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. Our goal is to identify new host genes that govern susceptibility to both OPC and HDC. This information 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. Individual differences in adaptive and innate immunity play a major role in determining whether or not a high-risk patient develops OPC or HDC. Our central hypothesis is that genetic variations in key immune effector genes underlie this differential susceptibility. As yet, the genetic variants that determine susceptibility to OPC and HDC are incompletely defined. Inbred strains of mice are ideal tools for identifying single genes that contribute to the development of complex phenotypes, such as susceptibility to candidiasis. Furthermore, high density single nucleotide polymorphism data for 15 inbred strains of mice are available. These data greatly facilitate the mapping of genetic loci that are associated with disease susceptibility. We have already found that 4 of these inbred mouse strains have significantly different susceptibility to OPC and HDC. In this proposal, we will study additional strains of mice and use the complementary methods of computational haplotype mapping and positional cloning to identify genetic loci that confer susceptibility to OPC and HDC. Our specific aims are: 1) To use computational haplotype mapping to identify genomic loci controlling murine susceptibility to OPC and HDC; 2) To use positional cloning from a cohort of F2 intercross progeny of susceptible and resistant strains of mice to identify quantitative trait loci that govern susceptibility to candidiasis; and 3) To characterize polymorphic variations in positional candidate genes identified in Aims 1 and 2. The results of these studies will provide a solid foundation for future investigations to determine the mechanisms by which these genetic loci influence susceptibility to OPC and HDC. The strong homology and synteny between the murine and human genomes provides a high probability that the results of these experiments will be applicable to humans. In the longer term, identifying the genetic basis for susceptibility to OPC and HDC will enable the use of more targeted prophylactic strategies and perhaps new treatment modalities for these diseases. PUBLIC HEALTH RELEVANCE: 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.