Mining slime mold for susceptibility genes to fungi

描述（由申请人提供）：真菌性疾病是当前医疗实践中的主要临床问题。宿主遗传学与宿主易感性之间的关系是医学真菌学领域一个尚未解决的问题。虽然有间接证据表明，对真菌病的易感性是由宿主遗传因素决定的，但这一领域相对未被探索。目前用于鉴定哺乳动物中的抗性和易感基因的技术是繁琐、缓慢和低效的，并且迫切需要新的方法。对于人类真菌病，使用标准遗传学方法的困难由于许多类型的真菌疾病在人群中发生频率相对较低的事实而加剧。我们的实验室最近已经确定，人类致病真菌新型隐球菌与变形虫捕食者卡氏阿米巴和Dictostyrophiddiscoideum的相互作用是非常相似的哺乳动物巨噬细胞所观察到的。我们的研究表明，C. neoformans可以感染D.盘状突，在细胞内复制，并杀死变形虫细胞。D. discoideum是一种黏菌，其已被证明是用于研究诸如趋化性和细胞间信号传导的细胞过程的极其有用的系统。D. discoideum可以作为C. neoformans提供了使用这种遗传可塑性阿米巴宿主来剖析简单真核生物中宿主-病原体相互作用的机会。本申请提出利用该系统来识别D. discoideum易感性和抗性基因，可以导致在巨噬细胞中同源哺乳动物基因的鉴定。我们预计，这种方法的新奇与D。discoideum系统将导致从标准真菌-巨噬细胞实验中不能立即明显的遗传途径的鉴定。

DESCRIPTION (provided by applicant): Fungal diseases are a major clinical problem in current medical practice. A major unsolved problem in the field of medical mycology is the relationship between host genetics and host susceptibility. Although there is circumstantial evidence that susceptibility to fungal diseases is determined by host genetic factors, this area is relatively unexplored. Current technologies for identifying resistance and susceptibility genes in mammals are cumbersome, slow, and inefficient and, new approaches are urgently needed. For human mycoses the difficulties in using standard genetic approaches are compounded by the fact that many types of fungal diseases occur at relatively low frequency in human populations. Our laboratory has recently established that the interactions of the human pathogenic fungus Cryptococcus neoformans with the ameboid predators Acanthamoeba castellani and Dictostylium discoideum are very similar to that observed with mammalian macrophages. Our group has shown that C. neoformans can infect D. discoideum, replicate intracellularly, and kill the amoeboid cells. D. discoideum is a slime mold, which has proven to be an extremely useful system for the studying such cellular processes as chemotaxis and cell-to-cell signaling. The fact that D. discoideum can be host for C. neoformans provides the opportunity to use this genetically malleable ameboid host to dissect host-pathogen interactions in a simple eukaryote. This application proposes to exploit this system to identify D. discoideum susceptibility and resistance genes that can lead to the identification of homologous mammalian genes in macrophages. We anticipate that the novelty of this approach combined with the experimental versatility of the D. discoideum system will lead to the identification of genetic pathways that are not immediately obvious from standard fungal-macrophage experiments.