Cellular and molecular mechanisms of host resistance to Toxoplasma gondii

描述(申请人提供)：弓形虫是一种全球分布的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风险。这种专性寄生虫通常只对免疫功能受损的人造成多器官衰竭，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，往往会发生流产或胎儿畸形。IL-12和干扰素-2的共同作用是弓形虫耐药的核心。我们最近发现TLR11在感知弓形虫、调节IL-12的产生和激活T细胞介导的对该寄生虫的反应中起主导作用。与此同时，TLR11在人类中只由一个非功能性假基因表达，而人类在缺乏TLR11的情况下如何发生先天和获得性免疫反应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TLR11非依赖的IL-12诱导中的作用；2)在缺乏TLR11的情况下，确定NK、CD4和CD8 T细胞在依赖干扰素的宿主抵抗弓形虫中的作用；以及3)确定TLR11系统和粘膜非依赖性免疫应答弓形虫的异同。这些研究有望确定TLR11非依赖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弓形虫保护性疫苗的动物模型至关重要，也可能是针对其他顶丝复合体寄生虫。 与公共卫生相关：原生动物寄生虫弓形虫是一种普遍分布的病原体，全世界有超过10亿人感染。这项建议的目的是确定在没有TLR11(一种与人类弓形虫病相关的情况)的情况下，如何诱导和调节对弓形虫的先天性和获得性免疫。通过这项建议中描述的实验，我们希望获得所需的知识，以开发针对弓形虫和其他原生动物寄生虫的安全有效的疫苗策略。

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.