Mucosal immunity to Toxoplasma gondii

对弓形虫的粘膜免疫

• 批准号: 10390295
• 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
• 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/10390295
• 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; Persons; 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 inflammation; gut microbiota; immunopathology; innovation; macrophage; microbiota; mouse model; neutrophil; novel; prenatal; response; screening; sensor; stillbirth

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 弓形虫是一种常见的食源性致病菌。据估计，仅在美国就有150万人 每年感染弓形虫，这种原生动物寄生虫是第二流行的致命 美国的食源性病原体。我们的研究比较了弓形虫感染的属菌(无菌)动物 对常规小鼠的免疫刺激信号已经证实是由共生菌诱导的 对寄生虫感染的结果有重大影响。我们还发现，微生物区系可增强干扰素-γ 通过TLR接头蛋白MyD88的反应和肠道炎症。我们假设协同效应 微生物群和寄生虫的先天感知调节干扰素-γ依赖的宿主抵抗和 免疫病理学。我们建议在这些发现的基础上，对先天如何 在弓形虫感染过程中，微生物区系的识别影响干扰素-γ的产生，参与了哪些细胞类型 产生保护性和免疫病理干扰素-γ，以及弓形虫和 微生物区系驱动的干扰素-γ。提议的项目是创新的，因为它考察了一种新的思考方式 在微生物区系存在的情况下宿主与寄生虫的相互作用。它汇集了弓形虫的自然模型 感染，参与感知寄生虫和微生物区系的先天免疫受体，以及调节 感染部位干扰素-γ的产生。在目标1中，我们将使用小鼠模型和体外筛选 弓形虫中调节依赖微生物区系的干扰素-γ产生的天然免疫感受器的鉴定 感染。在目标2中，我们将确定先天免疫细胞和获得性免疫细胞在 干扰素-γ依赖的宿主防御和肠道病理。在《目标3》中，我们将 确定潘氏细胞的影响 从确定弓形虫诱导Paneth细胞的生化途径探讨弓形虫诱导的肠道致病机制 死亡，并通过定义Paneth细胞丢失在弓形虫触发的肠道致病中的作用 潘氏细胞报告基因和潘氏细胞缺陷小鼠是我们实验室培育的。这些研究将推动我们的 了解干扰素-γ在弓形虫感染中的保护作用和病理作用。