Cellular and molecular mechanisms of host resistance to Toxoplasma gondii

描述（由申请人提供）：刚地弓形虫是一种分布在世界各地的细胞内原生动物寄生虫。根据地理区域的不同，30-70%的人口感染了这种寄生虫，基本上整个人口都有感染的危险。这种专性寄生虫通常只在免疫功能低下的个体中导致多器官衰竭，特别是那些患有艾滋病的人，但如果在怀孕期间感染弓形虫，通常会发生流产或胎儿异常。IL-12和IFN-的共同作用是抵抗弓形虫的核心。我们最近发现，TLR11在感知弓形虫、调节IL-12的产生和激活T细胞介导的对弓形虫的反应中起主导作用。同时，TLR11在人类中仅由一个无功能的假基因代表，并且在TLR11缺失的情况下，人类先天和适应性免疫反应如何发生的主要问题仍未得到解答。本项目的总体目标是：1)确定中性粒细胞、巨噬细胞和dc在调节不依赖tlr11诱导IL-12中的作用；2)在TLR11缺失的情况下，确定NK、CD4和CD8 T细胞在IFN依赖性宿主对弓形虫的抗性中的作用；3)鉴定对弓形虫的全身和粘膜tlr11非依赖性免疫反应的异同。这些研究有望确定不依赖tlr11的宿主对弓形虫的抗性机制。此外，这些研究对于建立适合设计针对弓形虫和其他顶复体寄生虫的保护性疫苗的动物模型至关重要。

DESCRIPTION (provided by applicant): Toxoplasma gondii is an intracellular protozoan parasite that has a worldwide distribution. Depending on the geographic area, 30-70% of the human population is infected with this parasite, and essentially the entire human population is at risk of infection. This obligate parasite is usually responsible for multi-organ failure only in immunocompromised individuals, especially those afflicted with AIDS, but if infection with T. gondii occurs during pregnancy, abortion or fetal abnormalities often occur. The combined efforts of IL-12 and IFN- are central to resistance to T. gondii. We have recently established that TLR11 plays a dominant role in sensing T. gondii, regulating IL-12 production, and activating T cell-mediated responses to the parasite. Concomitantly, TLR11 is represented in humans only by a non-functional pseudogene, and the major question of how human innate and adaptive immune responses occur in the absence of TLR11 remains unanswered. The overall goals of this project are 1) to determine the roles of neutrophils, macrophages, and DCs in the regulation of TLR11-independent induction of IL-12; 2) to determine the roles of NK, CD4, and CD8 T cells in IFN--dependent host resistance to T. gondii in the absence of TLR11; and 3) to identify similarities and differences during systemic and mucosal TLR11-independent immune responses to T. gondii. These studies are expected to identify mechanisms of TLR11-independent host resistance to T. gondii. In addition, these studies are essential for establishing animal models suitable for the design of protective vaccines against T. gondii, and possibly against other apicomplexan parasites. PUBLIC HEALTH RELEVANCE: The protozoan parasite Toxoplasma gondii is a universally-distributed pathogen that infects over 1 billion people world-wide. The goal of this proposal is to determine how innate and adaptive immunity to T. gondii are induced and regulated in the absence of TLR11 (a situation relevant to human toxoplasmosis). Through the experiments described in this proposal, we expect to obtain the knowledge needed to develop strategies for safe and efficient vaccines against T. gondii and other protozoan parasites.