Cellular and molecular mechanisms of host resistance to Toxoplasma gondii

描述（由申请人提供）：弓形虫是一种细胞内原生动物寄生虫，在世界范围内分布。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低下的个体，特别是那些患有艾滋病的个体的多器官衰竭负责，但如果感染T。妊娠期发生弓形虫，常发生流产或胎儿畸形。IL-12和IFN-γ的共同作用是T细胞耐药的关键。刚地。我们最近发现TLR 11在T.弓形虫，调节IL-12的产生，并激活T细胞介导的对寄生虫的反应。同时，TLR 11在人类中仅由非功能性假基因代表，并且在TLR 11不存在的情况下人类先天性和适应性免疫应答如何发生的主要问题仍然没有答案。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TLR 11非依赖性诱导IL-12中的作用; 2）确定NK、CD 4和CD 8 T细胞在IFN-依赖性宿主对T细胞的抗性中的作用。在TLR 11不存在的情况下对弓形虫的免疫应答;以及3）鉴定对弓形虫的全身和粘膜TLR 11非依赖性免疫应答期间的相似性和差异。刚地。这些研究有望确定TLR 11非依赖性宿主对T.刚地。此外，这些研究对于建立适用于设计抗T.弓形虫，并可能对其他apicomplexan寄生虫。 公共卫生相关性：原生动物寄生虫弓形虫是一种普遍分布的病原体，感染了全世界超过10亿人。本研究的目的是确定先天性和适应性免疫对T.在TLR 11缺乏的情况下，弓形虫感染被诱导和调节（与人类弓形虫病相关的情况）。通过本提案中描述的实验，我们期望获得开发针对T.弓形虫和其他原生动物寄生虫。

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.