Genetics of susceptibility to candidiasis

描述（由申请方提供）：白色念珠菌引起粘膜和播散性疾病。口咽部念珠菌病（OPC）在许多患者尤其是HIV/AIDS患者中导致显著的发病率。血源性播散性念珠菌病（HDC）是一种医疗保健相关疾病，即使使用当前的抗真菌治疗，也会导致30 - 50%的死亡率。我们的目标是确定新的宿主基因，管理敏感性OPC和HDC。这些信息有望为宿主防御这些疾病的机制提供新的见解，并提供新的遗传方法来识别患有这些疾病的风险特别高的患者。 适应性免疫和先天免疫的个体差异在确定高危患者是否发生OPC或HDC方面起着重要作用。我们的中心假设是，关键免疫效应基因的遗传变异是这种差异易感性的基础。到目前为止，决定OPC和HDC易感性的遗传变异还没有完全确定。近交系小鼠是鉴定导致复杂表型发展的单个基因的理想工具，例如对念珠菌病的易感性。此外，15个近交系小鼠的高密度单核苷酸多态性数据可用。这些数据极大地促进了与疾病易感性相关的遗传位点的定位。我们已经发现这些近交系小鼠品系中的4个对OPC和HDC具有显著不同的易感性。在这个提议中，我们将研究更多的小鼠品系，并使用计算单倍型作图和定位克隆的互补方法来鉴定赋予OPC和HDC易感性的遗传位点。我们的具体目标是：1）使用计算单倍型作图来鉴定控制小鼠对OPC和HDC的易感性的基因组基因座; 2）使用来自小鼠的易感品系和抗性品系的F2杂交后代的队列的定位克隆来鉴定控制对念珠菌病的易感性的数量性状基因座;以及3）表征在目的1和2中鉴定的位置候选基因中的多态性变异。 这些研究的结果将为未来的研究提供坚实的基础，以确定这些遗传基因座影响对OPC和HDC易感性的机制。鼠和人基因组之间的强同源性和共线性提供了这些实验的结果将适用于人类的高概率。从长远来看，确定OPC和HDC易感性的遗传基础将使这些疾病能够使用更有针对性的预防策略，甚至可能是新的治疗方式。公共卫生相关性：这项研究与公共卫生高度相关，因为口咽念珠菌病是艾滋病毒/艾滋病患者的一个重要问题，特别是那些没有接受高效抗逆转录病毒治疗的患者。此外，血源性播散性念珠菌病在住院患者中很常见，即使经过治疗，仍然会导致显著的死亡率。发现控制口咽和播散性念珠菌病易感性的宿主基因有望为宿主防御这些疾病的机制提供新的见解，并提供新的遗传方法来识别患有这些疾病的风险特别高的患者。

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.