Mucosal immunity to Toxoplasma gondii

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 感染T.这种原生动物寄生虫是第二大流行致命的 食源性病原体在美国。我们对T.感染弓形虫的无菌动物 已经证实，由大肠杆菌诱导的免疫刺激信号 对寄生虫感染的结果有重大影响。我们还发现微生物群增强IFN-γ 反应和肠道炎症通过TLR衔接蛋白MyD88。我们假设协同作用 微生物群和寄生虫的先天感应调节IFN-γ依赖性宿主抗性的结果， 免疫病理学我们建议建立在这些发现的基础上，以获得一个机械的理解， 微生物群的识别影响T.弓形虫感染，涉及哪些细胞类型 产生保护性和免疫病理性IFN-γ，以及T.弓形虫和 微生物群驱动的IFN-γ。拟议的项目是创新的，因为它探讨了一种新的方式来思考 宿主-寄生虫在微生物群存在下的相互作用。它为T.弓形虫 感染，参与感应寄生虫和微生物群的先天免疫受体，以及调节 在感染部位产生IFN-γ。在目标1中，我们将使用小鼠模型和体外筛选 鉴定在T.弓形虫 感染在目标2中，我们将确定先天性和适应性免疫细胞在免疫系统中的细胞类型特异性贡献。 IFN-γ依赖的宿主防御和肠道病理学。在目标3中，我们 确定潘氏细胞的影响 在T上。通过定义T.刚地诱导潘氏细胞 死亡，并通过定义潘氏细胞损失对T.使用新的 潘氏细胞报告基因和潘氏细胞缺陷小鼠。这些研究将推动我们的 了解IFN-γ在T.弓形虫感染

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.