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Unravelling MyD88-dependent and independent mucosal immunity to Toxoplasma

揭示 MyD88 依赖性和独立的弓形虫粘膜免疫

基本信息

批准号：
10735738
负责人：
ERIC Y DENKERS
金额：
$ 42.31万
依托单位：
UNIVERSITY OF NEW MEXICO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-18 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735738
关键词：
Animals Biological Response Modifiers Cell physiology Cells Cessation of life Classification Cytokine Receptors Disease Epithelial Cells Epithelium Event Family Gastrointestinal tract structure Generations Health Health Hazards Helminths Host Defense Host Defense Mechanism Human Immune Immune response Immune system Immunity Immunocompromised Host Immunologic Deficiency Syndromes Immunologic Memory Infection Infection Control Inflammation Innate Immune Response Interferons Interleukin-1 Interleukin-12 Intestinal Mucosa Intestines Knockout Mice Lamina Propria Lead Life Lymphoid Cell Memory Molecular Motion Mouse Strains Mucosal Immune System Mucosal Immunity Mucous Membrane Mus Natural Immunity Oral Organism Organoids Outcome Parasites Pathology Pathway interactions Pattern Phenotype Population Production Public Health Receptor Signaling Research Research Personnel Resistance Resistance to infection Role Route Series Shapes Signal Transduction T memory cell T-Lymphocyte Toll-like receptor 11 Toll-like receptors Toxoplasma Toxoplasma gondii Toxoplasmosis Vaccinated Viral Work adaptive immunity biodefense cell type chronic infection congenital infection cytokine effector T cell emerging pathogen experimental study gastrointestinal epithelium gut microbiota host microbiota human pathogen improved insight intestinal epithelium knockout animal long term memory microbial microbiota novel opportunistic pathogen pathogen pathogenic microbe profilin receptor resistance mechanism response tool

项目摘要

Project Summary/Abstract The long-term objective of this proposal is to understand inductive and effector mechanisms of host defense in the intestinal mucosa. We use as a tool the intracellular protozoan Toxoplasma gondii, an orally acquired opportunistic pathogen inducing strong protective Th1- and IFN--based immunity and that is a significant health hazard in immunocompromised populations. Signaling through the adaptor molecule MyD88 is necessary for optimal initiation of immunity and resistance to this pathogen. While IL-1 family cytokine receptors use MyD88, the primary role of this signaling adaptor during T. gondii infection is believed to be in Toll-like receptor (TLR) signaling. Nevertheless, the particular TLR involved (TLR11/12) are not expressed in humans and indeed many other species, indicating presence of MyD88-independent pathways of immune initiation. Such pathways are also present in mice, insofar as infection of MyD88 knockout animals triggers robust, albeit delayed, Th1 responses in the intestinal mucosa. Additionally, MyD88 knockout mice can be vaccinated against lethal challenge with orally inoculated Toxoplasma. Open questions remain regarding the role of MyD88 in specific cell types and in the context of the intestine how the microbiota influences MyD88-dependent and MyD88-independent immunity during Toxoplasma infection. The central hypothesis underpinning our research is that MyD88-dependent pathways and MyD88-independent pathways work together to provide optimal immune initiation during infection. We will address this hypothesis focusing on interactions between cells of the lamina propria, Toxoplasma and the host microbiota. Using our hypothesis to guide us, we will pursue three specific aims. Aim 1: Determine the role of intestinal epithelial cells in initiation of immunity and control of Toxoplasma. Using intestinal organoids we will examine how epithelial cells respond to infection, and how this impacts responses in the lamina propria compartment. The influence of epithelial MyD88 in immunity to T. gondii will be determined. Aim 2: Identify how MyD88 impacts innate lymphoid cell (ILC) function during Toxoplasma infection. The activity of ILC, with a focus on ILC1 and ILC3, will be examined using mouse strains deficient in ILC populations and strains with deletion of MyD88 in ILC. Aim 3: Determine the influence of MyD88 expression on generation of mucosal T cell effector and memory function. The requirement for MyD88 in lamina propria T cells will be determined with regard to short term effector function and long-term memory function. The importance of this research is that it will significantly extend and deepen our understanding of mechanisms of resistance to Toxoplasma within the mucosal immune system, which is critical to understanding mucosal 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 infection with Toxoplasma and other microbial pathogens that threaten human health.

项目总结/摘要本提案的长期目标是了解宿主的诱导和效应机制，肠粘膜的防御。我们使用细胞内的弓形虫作为工具，获得性机会致病菌诱导强保护性Th 1和IFN-γ免疫，免疫功能低下人群中的重大健康危害。通过衔接分子的信号传导 MyD 88对于免疫和抵抗这种病原体的最佳起始是必需的。IL-1家族细胞因子受体使用MyD 88，这是T.弓形虫感染是 Toll样受体（TLR）信号通路。然而，涉及的特定TLR（TLR 11/12）在人类和许多其他物种中不表达，表明存在MyD 88非依赖性的免疫启动的途径。这种途径也存在于小鼠中，只要感染MyD 88 敲除动物在肠粘膜中触发了强有力的，尽管是延迟的Th 1应答。此外，本发明还 MyD 88基因敲除小鼠可以接种疫苗以对抗口服接种的弓形虫的致死性攻击。开放关于MyD 88在特定细胞类型中的作用以及在肠道中的作用，弓形虫感染期间微生物群影响MyD 88依赖性和MyD 88非依赖性免疫感染支撑我们研究的中心假设是MyD 88依赖性通路和 MyD 88独立途径共同作用，在感染期间提供最佳的免疫启动。我们将解决这一假设的重点是细胞之间的相互作用，固有层，弓形虫和宿主微生物群利用我们的假设来指导我们，我们将追求三个具体目标。目标1：确定肠上皮细胞在启动免疫和控制弓形虫中的作用。使用肠我们将研究上皮细胞如何对感染做出反应，以及这如何影响类器官中的反应。固有层隔室。上皮细胞MyD 88对T.将确定是否感染弓形虫。目的2：确定MyD 88在弓形虫感染期间如何影响先天淋巴细胞（ILC）功能。的将使用ILC缺陷的小鼠品系检测ILC的活性，重点是ILC 1和ILC 3 ILC中MyD 88缺失的群体和菌株。目的3：确定MyD 88表达的影响对黏膜T细胞效应子的产生和记忆功能的影响。固有层对MyD 88的需求将关于短期效应功能和长期记忆功能来确定T细胞。的这项研究的重要性在于，它将大大扩展和加深我们对机制的理解在粘膜免疫系统中对弓形虫的抗性，这对于理解粘膜免疫系统至关重要。人体的宿主防御这项研究的最终影响是，它可以预期确定新的在弓形虫和其他寄生虫感染期间促进抵抗力和免疫力的寄生虫和宿主靶标微生物病原体威胁人类健康。