MyD88-independent resistance to Toxoplasma in the intestine

MyD88 独立的肠道内对弓形虫的抵抗力

• 批准号: 10393513
• 负责人: ERIC Y DENKERS
• 金额: $ 37.59万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-18 至 2023-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393513
• 关键词: Affect; Attention; Automobile Driving; Bacterial Infections; Bone Marrow; CD4 Positive T Lymphocytes; Cell Lineage; Cell physiology; Cells; Cellular Immunity; Characteristics; Communicable Diseases; Dendritic Cells; Disease; Effector Cell; Generations; Hand; Host Defense; Human; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunocompromised Host; Infection; Inflammation; Inflammatory; Interferon Type II; Interleukin-12; Intestinal Mucosa; Intestines; Knockout Mice; Knowledge; Lamina Propria; Lead; Life; MYD88 deficiency; Microbe; Modeling; Molecular; Mucous Membrane; Mus; Opportunistic Infections; Oral; Osteomyelitis; Parasites; Pathway interactions; Phase; Phenotype; Population; Production; Proteins; Public Health; Receptor Cell; Research; Research Proposals; Resistance; Resistance to infection; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Small Intestines; Source; Specificity; T cell response; T memory cell; T-Lymphocyte; Tamoxifen; Testing; Th1 Cells; Tissues; Toll-like receptor 11; Toll-like receptors; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Uracil; Vaccinated; Vaccination; Vaccine Design; Work; antimicrobial; base; biodefense; congenital infection; cytokine; effector T cell; human disease; immune activation; improved; knockout animal; macrophage; microbial; microbicide; monocyte; mouse model; novel; opportunistic pathogen; oral infection; pathogen; profilin; receptor; recruit; response; tool; vaccine immunotherapy

Project Summary/Abstract The long-term objective of this proposal is to understand induction and effector mechanisms of immunity in the absence of signaling adaptor MyD88. We use as a tool the intracellular protozoan Toxoplasma gondii, an orally acquired opportunistic pathogen that normally induces strong protective Th1- and IFN-γ-based immunity. Toxoplasma can activate mouse immunity through an MyD88-dependent TLR11/12 pathway. Yet, humans lack these TLR and populations deficient in MyD88 expression retain resistance to all but a limited number of bacterial infections. Therefore, immune pathways that do not involve MyD88 are important to understand. We have found that MyD88 knockout mice are capable of generating Th1-like immunity during Toxoplasma infection, indicating that alternative pathways for immune initiation are active in the mouse model. In addition, MyD88 knockout animals can be vaccinated against lethal infection with orally inoculated T. gondii. The cell and molecular mechanisms underpinning MyD88-independent immunity are uncharacterized. The central hypothesis driving this research proposal is that the mouse immune system is equipped to generate protective immunity to Toxoplasma using MyD88-independent pathways of resistance. We more generally hypothesize that this is important for understanding human disease based upon overall resistance to infections in the absence of MyD88. Three Specific Aims will be used to understand MyD88-independent immunity during infection. Aim 1: Determine how T cells are activated in the absence of MyD88 signaling in the mucosal response to Toxoplasma. We will investigate cytokine requirements for MyD88-independent generation of IFN-γ-positive T cells and characterize the phenotype and specificity of these cells. Aim 2: Determine the impact of MyD88 deficiency on gut microbicidal effector functions. We will examine how deficiency in this signaling adaptor affects recruitment and function of anti- microbial effector cells in the intestinal mucosa following Toxoplasma infection. Aim 3: Determine how vaccination with an avirulent Toxoplasma strain triggers MyD88-independent protective immunity in the intestinal mucosa. We will employ a nonproliferating Toxoplasma strain to determine how T. gondii induces resistance to lethal oral challenge in a model where immunity can be triggered without complications associated with parasite-induced tissue damage. The importance of this research is that it will significantly extend and deepen our understanding of induction and effector mechanisms of immunity in the absence of MyD88, which is critical to understanding host defense in humans. The ultimate impact of this research is that it can be expected to identify novel parasite and host targets for promoting resistance and immunity during infectious disease.

项目总结/摘要 这项提案的长期目标是了解免疫的诱导和效应机制 在不存在信号转导衔接子MyD 88的情况下。我们使用细胞内的弓形虫作为工具， 一种口服获得性机会致病菌，通常诱导基于Th 1和IFN-γ的强保护性 免疫力弓形虫可以通过MyD 88依赖的TLR 11/12途径激活小鼠免疫。然而， 人类缺乏这些TLR，MyD 88表达缺陷的群体保留了对所有疾病的抗性， 细菌感染的数量。因此，不涉及MyD 88的免疫途径对于 明白我们发现MyD 88基因敲除小鼠在免疫过程中能够产生Th 1样免疫。 弓形虫感染，表明免疫启动的替代途径在小鼠中是活跃的 模型此外，MyD 88敲除动物可以口服接种抗致死性感染的疫苗。 T.刚地。支持MyD 88非依赖性免疫的细胞和分子机制是 没有特征的推动这项研究的中心假设是，小鼠的免疫系统 配备了使用MyD 88-独立途径产生对弓形虫的保护性免疫的设备， 阻力我们更普遍地假设，这对于理解人类疾病很重要， 在缺乏MyD 88的情况下对感染的总体抗性。三个具体目标将用于 了解感染期间MyD 88的非依赖性免疫。目的1：确定T细胞如何被激活， 在对弓形虫的粘膜应答中缺乏MyD 88信号传导。我们将研究细胞因子 IFN-γ阳性T细胞的MyD 88非依赖性产生的要求并表征表型 和特异性。目的2：确定MyD 88缺陷对肠道杀微生物效应物的影响 功能协调发展的我们将研究这种信号衔接子的缺陷如何影响抗- 弓形虫感染后肠粘膜中的微生物效应细胞。目标3：确定如何 用无毒力弓形虫株接种疫苗在小鼠中触发MyD 88非依赖性保护性免疫， 肠粘膜我们将使用一个非增殖的弓形虫菌株，以确定如何T。弓形虫诱导 在可触发免疫而无并发症的模型中对致死性口服攻击的抗性 与寄生虫引起的组织损伤有关这项研究的重要性在于， 扩展和加深我们对免疫诱导和效应机制的理解， MyD 88，这对理解人类的宿主防御至关重要。这项研究的最终影响是 它有望发现新的寄生虫和宿主靶点，以促进抗性和免疫力 在传染病期间。