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

基本信息

批准号：
8616022
负责人：
Felix Yarovinsky
金额：
$ 39.35万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616022
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

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

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项目摘要

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.

描述（由申请人提供）：弓形虫Gondii是一种具有全球分布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，从本质上讲，整个人口都有感染的风险。这种强制性寄生虫通常仅在免疫功能低下的个体中造成多器官失败，尤其是患有艾滋病的人，但是如果在怀孕期间出现T. gondii的感染，经常发生堕胎或胎儿异常。 IL-12和IFN-的综合努力是对巨杆菌抗性的核心。我们最近确定，TLR11在传感t. gondii，调节IL-12产生并激活T细胞介导的对寄生虫的反应中起着主要作用。同时，TLR11仅以非功能性假基因为代表，而在没有TLR11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。该项目的总体目标是1）确定中性粒细胞，巨噬细胞和DC在TLR11独立诱导IL-12诱导中的作用； 2）在没有TLR11的情况下，确定NK，CD4和CD8 T细胞在IFN依赖性宿主对T. gondii的抗性中的作用； 3）在全身和粘膜TLR11无依赖性的免疫反应中确定相似性和差异。这些研究有望确定与TLR11无关的宿主对T. gondii的抗性的机制。此外，这些研究对于建立适合于针对gondii的保护性疫苗的动物模型至关重要。