Cellular and molecular mechanisms of host resistance to Toxoplasma gondii

宿主抵抗弓形虫的细胞和分子机制

• 批准号: 8423397
• 负责人: Felix Yarovinsky
• 金额: $ 36.99万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8423397
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Adaptor Signaling Protein; Animal Model; Animals; Antigen Presentation; Binding; Biochemical; Blood; CD8B1 gene; Cells; Central Nervous System Infections; Data; Development; Disease; Environment; Experimental Models; Fetus; Gene Targeting; Geographic Locations; Goals; HIV Infections; Host Defense; Host Defense Mechanism; Host resistance; Human; Immune; Immune response; Immune system; Immunocompromised Host; Individual; Infection; Interferons; Interleukin-12; Knowledge; Laboratories; Masks; Mediating; Modeling; Molecular; Mus; Natural Immunity; Natural Killer Cells; Organ failure; Parasites; Persons; Phenotype; Physiological; Play; Population; Pregnancy; Production; Pseudogenes; Regulation; Research; Resistance; Risk; Role; Signal Transduction; Specificity; T-Lymphocyte; Techniques; Testing; Time; Toll-like receptors; Toxoplasma gondii; Toxoplasmosis; Vaccines; abortion; adaptive immunity; base; cell mediated immune response; cytokine; design; disorder risk; fetal; innovation; macrophage; neutrophil; pathogen; profilin; programs; public health relevance; research study; response; tool

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.

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，并且基本上整个人口都面临感染的风险。这种专性寄生虫通常仅在免疫功能低下的个体中引起多器官衰竭，尤其是那些患有艾滋病的人，但如果在怀孕期间感染弓形虫，则经常会发生流产或胎儿畸形。 IL-12 和 IFN-的共同作用对于弓形虫的抵抗至关重要。我们最近确定 TLR11 在感知弓形虫、调节 IL-12 产生以及激活 T 细胞介导的寄生虫反应方面发挥着主导作用。与此同时，TLR11 在人类中仅由无功能的假基因代表，而人类先天性和适应性免疫反应如何在没有 TLR11 的情况下发生的主要问题仍未得到解答。该项目的总体目标是 1) 确定中性粒细胞、巨噬细胞和 DC 在调节不依赖 TLR11 的 IL-12 诱导中的作用； 2) 确定 NK、CD4 和 CD8 T 细胞在缺乏 TLR11 的情况下 IFN 依赖性宿主对弓形虫的抗性中的作用； 3) 确定对弓形虫的系统性和粘膜 TLR11 独立免疫反应的相似性和差异。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以及可能针对其他顶复门寄生虫的保护性疫苗的动物模型至关重要。