Mucosal immunity to Toxoplasma gondii

对弓形虫的粘膜免疫

基本信息

批准号：
9913455
负责人：
Felix Yarovinsky
金额：
$ 45.99万
依托单位：
UNIVERSITY OF ROCHESTER
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：
2018-05-10 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9913455
关键词：
Adaptor Signaling Protein Animals Attention B-Lymphocytes Bacteria Biochemical Pathway Biological Assay Birth Brain Injuries Cell Death Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Complex Defect Dendritic Cells Ensure Epithelial Cells Escherichia Escherichia coli Eye Feedback Germ-Free Gnotobiotic Goals Health Host Defense Host resistance Immune Immune response Immunity Immunologic Receptors In Vitro Infection Inflammatory Innate Immune System Interferon Type II Interferons Intestines Laboratories Lead Lymphoid Cell Mediating Modeling Molecular Mucosal Immune System Mucosal Immunity Mucous Membrane Mus MyD88 protein Natural Killer Cells Outcome Paneth Cells Parasites Parasitic infection Pathogenesis Pathologic Pathology Physiological Play Predisposition Pregnancy Production Proteobacteria Reaction Reporter Role Signal Transduction Site Source Symptoms T-Cell Activation T-Lymphocyte Testing Toxoplasma gondii Toxoplasmosis United States antimicrobial peptide cell type commensal bacteria cytokine dysbiosis foodborne pathogen gut microbiota immunopathology inflammatory disease of the intestine innovation macrophage microbiota mouse model neutrophil novel prenatal response screening sensor stillbirth

项目摘要

Project Summary Toxoplasma gondii is a common food borne pathogen. It is estimated that 1.5 million people in the U.S. alone become infected with T. gondii annually and this protozoan parasite is the second most prevalent deadly foodborne pathogen in United States. Our studies comparing T. gondii infected gnotobiotic (germ-free) animals to conventional mice have established that the immunostimulatory signals induced by commensal bacteria have major effects on the outcomes of the parasitic infections. We also found that microbiota potentiates IFN-γ responses and intestinal inflammation via the TLR adaptor protein MyD88. We hypothesize that synergistic innate sensing of microbiota and the parasite regulates the outcome of IFN-γ dependent host resistance and immunopathology. We propose to build upon these findings to gain a mechanistic understanding of how innate recognition of microbiota influences IFN-γ production during T. gondii infection, what cell types are involved in producing protective and immunopathological IFN-γ, and the physiological consequences of T. gondii and microbiota-driven IFN-γ. The proposed project is innovative because it examines a new way to think about host-parasite interactions in the presence of microbiota. It brings together a natural model for T. gondii infection, innate immune receptors involved in sensing parasite and microbiota, and mechanisms that regulate the production of IFN-γ at the sites of infection. In Aim 1, we will use mouse models and in vitro screening assays to identify innate immune sensors that regulate microbiota-dependent IFN-γ production during T. gondii infection. In Aim 2, we will determine cell type-specific contributions of innate and adaptive immune cells in IFN-γ-dependent host defense and intestinal pathology. In Aim 3, we will determine the impact of Paneth cells on T. gondii-induced intestinal pathogenesis by define biochemical pathways for T. gondii-induced Paneth cell death, and by defining the effects of Paneth cell loss on T. gondii-triggered intestinal pathogenesis using novel Paneth cell reporter and Paneth cell-deficient mice generated in our lab. These studies will advance our understanding of the protective and pathological effects of IFN-γ during T. gondii infection.

项目摘要弓形虫弓形虫是一种常见的食物传播病原体。据估计，仅在美国，有150万人每年被T. gondii感染，而这种原生动物寄生虫是第二大普遍的致命美国食源性病原体。我们的研究比较了弓形虫感染的gnotobiotic（无菌）动物对于常规小鼠已经确定，共生细菌诱导的免疫刺激信号对寄生虫感染的结果有重大影响。我们还发现菌群增强IFN-γ 通过TLR衔接蛋白MYD88的反应和肠道注射。我们假设这种协同作用微生物群和寄生虫的先天敏感性调节IFN-γ依赖性宿主抗性和免疫病理学。我们建议以这些发现为基础识别菌群会影响T. gondii感染期间的IFN-γ产生，涉及哪些细胞类型产生受保护和免疫病理的IFN-γ，以及T. gondii和微生物群驱动的IFN-γ。拟议的项目具有创新性，因为它研究了一种新的思考方式在菌群存在下的宿主 - 寄生虫相互作用。它汇集了T. gondii的天然模型感染，涉及寄生虫和微生物群的先天免疫受体以及调节的机制在感染部位的IFN-γ产生。在AIM 1中，我们将使用鼠标模型和体外筛选测定鉴定先天性免疫剂，以调节T. gondii期间微生物群的IFN-γ产生在AIM 2中，我们将确定先天和适应性免疫细胞在细胞类型中的特定贡献 IFN-γ依赖性宿主防御和肠道病理学。在AIM 3中，我们将确定Paneth细胞的影响在T. gondii诱导的肠道发病机理上，通过定义的gondii诱导的Paneth细胞的生化途径死亡，并通过定义Paneth细胞丢失对使用新颖的肠触发肠道发病机理的影响 Paneth Cell Reporter和Paneth细胞缺陷小鼠在我们的实验室中产生。这些研究将推动我们的理解gondii感染期间IFN-γ的受保护和病理作用。