Strain-specific host-pathogen interactions in toxoplasmosis

描述（由申请人提供）：刚地弓形虫是美国和世界范围内人类和牲畜的严重病原体。除了众所周知的对发育中的胎儿的致病能力外，在过去的二十年里，这种原生动物寄生虫因其可导致艾滋病患者的致命疾病而臭名昭著。许多研究表明，动物和人的疾病结果取决于引起感染的寄生虫菌株。了解这些差异的基础对于使治疗与感染的具体情况相匹配具有重要的临床意义。例如，一些菌株可能通过过度的免疫反应而不是通过寄生虫本身直接破坏组织而产生最严重的后果。相反，其他菌株可能具有很强的侵入性，导致免疫反应跟不上，因此患者被寄生虫淹没。治疗这两种情况需要完全不同的策略：在一种情况下，类固醇或其他免疫抑制治疗可能是最佳选择，而在另一种情况下，免疫系统可能需要得到帮助，而不是受损，并且需要使用抗寄生虫药物进行快速治疗。我们工作的目标是了解宿主-病原体相互作用中菌株特异性差异的分子基础。我们的方法是结合体外和体内研究来比较不同的菌株，从而获得不同表型背后的现象学的详细理解。我们使用全基因组分析不同菌株如何与受感染的宿主细胞相互作用，以及使用允许在活体动物中以非侵入性方式监测感染的方法跟踪疾病确切进展的详细体内分析。一旦确定了这些表型，我们使用不同弓形虫菌株之间的杂交来绘制相关基因。最后，我们采用分子遗传学和细胞生物学相结合的方法来验证候选基因的参与，并确定其作用机制，特别关注不同的等位基因如何在致病特性上发挥差异。

DESCRIPTION (provided by applicant): Toxoplasma gondii is a serious pathogen of humans and livestock in the U.S.A. and world-wide. In addition to its well-known disease-causing abilities in the developing fetus, in the past two decades this protozoan parasite has increased its notoriety through the fatal disease it can cause in AIDS patients. Many studies have shown that the disease outcome in animals and probably people is dependent on which strain of the parasite is responsible for the infection. Knowing the basis for these differences is of great clinical importance in allowing the treatment to be matched to the specifics of the infection. For example, some strains may produce the most serious consequences through an excessive immune response rather than through direct tissue destruction by the parasite itself. Conversely, other strains may be so invasive that the immune response can't keep up and so the patient is overwhelmed by the parasite. Treating these two scenarios requires completely different strategies: in one, steroids or other immunosuppressive treatments might be the best choice while in the other, the immune system may need to be helped, not impaired, and rapid treatment with anti-parasite agents is needed. The goal of our work is to understand the molecular basis for strain-specific differences in the host-pathogen interaction. Our approach has been to use a combination of in vitro and in vivo studies to compare different strains and thereby acquire a detailed understanding of the phenomenology behind the different phenotypes. We use genome-wide analysis of how different strains interact with the infected host cell as well as detailed in vivo analysis that follows the exact progression of disease using methods that allow the infection to be monitored in live animals in a non-invasive way. Once these phenotypes are determined, we use crosses between the different strains of Toxoplasma to map the genes involved. Finally, we employ a combination of molecular genetic and cell biological approaches to verify the involvement of the candidate genes and determine the mechanism of their action with special attention to how the different alleles play out as differences in disease-causing properties.