MyD88-independent resistance to Toxoplasma in the intestine

MyD88 独立的肠道内弓形虫抵抗力

• 批准号: 9915889
• 负责人: ERIC Y DENKERS
• 金额: $ 37.63万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9915889
• 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; 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.

项目摘要/摘要 该提议的长期目标是了解免疫的归纳和效应器机制 在没有信号适配器myd88的情况下。我们用作细胞内原生动物弓形虫的工具， 一种通常诱导强烈保护性Th1-和IFN-γ的口头上获得的机会性病原体 免疫。弓形虫可以通过MyD88依赖性TLR11/12途径激活小鼠免疫。然而， 人类缺乏这些TLR和MyD88表达不足的种群，除了有限 细菌感染的数量。因此，不涉及MYD88的免疫途径对 理解。我们发现MyD88淘汰小鼠能够在期间产生Th1般的免疫力 弓形虫感染，表明免疫倡议的替代途径在小鼠中有效 模型。此外，MyD88敲除动物可以通过口服接种致死感染接种致死感染 T. Gondii。支持MyD88独立免疫的细胞和分子机制是 未表征。推动该研究建议的中心假设是小鼠免疫系统 相当于使用MyD88独立的途径对弓形虫产生受保护的免疫力 反抗。我们更普遍地假设这对于理解基于人类疾病的重要 在没有MyD88的情况下对感染的总体抵抗力。三个具体目标将用于 了解感染过程中独立于MyD88的免疫力。目标1：确定如何在 粘膜对弓形虫的粘膜反应中没有MyD88信号传导。我们将研究细胞因子 非独立于MyD88的IFN-γ阳性T细胞的要求，并表征了表型 这些细胞的特异性。 AIM 2：确定MyD88缺乏对肠道微生物效应器的影响 功能。我们将研究该信号适配器中的缺乏症如何影响抗 - 的募集和功能 弓形体感染后肠粘膜中的微生物效应细胞。目标3：确定如何 具有抗毒剂毒素菌株的疫苗接种触发了MyD88独立的保护免疫 肠粘膜。我们将采用非增殖的弓形虫菌株来确定T. gondii如何诱导 在可以触发免疫力而不会并发症的模型中，对致命口服挑战的抵抗力 与寄生虫诱导的组织损伤有关。这项研究的重要性是它将大大 在没有的情况下，扩展并加深了我们对免疫的归纳和效应机制的理解 MYD88，这对于了解人类的宿主防御至关重要。这项研究的最终影响是 可以期望确定新颖的寄生虫和宿主目标以促进抗药性和免疫力 在传染病期间。