Basis of MyD88-independent Th1 immunity during Toxoplasma infection

 描述（由申请人提供） 该提案的长期目标是了解先天免疫如何识别和响应微生物感染，以推动适应性免疫的出现。该项目的重点是小鼠感染原生动物寄生虫弓形虫，一种病原体触发强大的Th 1免疫，通常使宿主生存和寄生虫包囊在中枢神经系统内。以前的工作已经确定了Toll样受体（TLR）-MyD 88信号通路的参与，驱动树突状细胞IL-12的产生，有助于激活保护性T细胞和控制感染。在该提议中，中心假设是弓形虫的MyD 88非依赖性识别是导致对感染的适应性免疫的重要替代途径。这得到了缺乏MyD 88的小鼠的初步数据的支持，这些数据显示在用减毒弓形虫接种疫苗后出现了致敏的T细胞和对感染的免疫力。将以两个具体目标来检验这一假设。目的1：确定TLR/IL-12信号传导是否是在MyD 88不存在的情况下保护性免疫所必需的。将通过与Myd 88-/-背景的遗传杂交产生一组敲除小鼠，这将使我们能够确定MyD 88-非依赖性TLR信号传导和MyD 88-非依赖性IL-12在对感染的适应性免疫中的参与。目的2：确定炎性单核细胞是否驱动MyD 88非依赖性保护性免疫。我们假设，以其对T。弓形虫是MyD 88-独立的适应性免疫的未被识别的驱动因素。将使用体内mAb细胞消耗和我们将为此目的产生的Myd 88-/- IL-12-eYFP报告基因小鼠的分析来测试该假设。这项研究的重要性在于，我们将生成关于驱动适应性免疫的未经研究的MyD 88独立途径的数据。这可能会对理解人类免疫力产生影响，因为MyD 88缺陷的人群对所有感染都有抵抗力，但范围很窄。因此，该项目的实际意义在于，我们期望在感染和炎症期间为疫苗开发和免疫治疗确定新的靶标。

 DESCRIPTION (provided by applicant) The long-term objective of this proposal is to understand how innate immunity recognizes and responds to microbial infection to drive emergence of adaptive immunity. The project focuses on mouse infection with the protozoan parasite Toxoplasma gondii, a pathogen triggering strong Th1 immunity that normally enables host survival and parasite encystment within the central nervous system. Previous work has established involvement of Toll-like receptor (TLR)-MyD88 signaling pathways driving dendritic cell IL-12 production that contributes to activation of protective T cells and control of infection. In this proposal the central hypothesis is that MyD88-independent recognition of Toxoplasma is an important alternative pathway leading to adaptive immunity to infection. This is supported by preliminary data in mice lacking MyD88 showing emergence of primed T cells and immunity to infection after vaccination with attenuated Toxoplasma. The hypothesis will be tested with two specific aims. Aim 1: Determine if TLR/IL-12 signaling is required for protective immunity in the absence of MyD88. A panel of knockout mice will be created by genetic crossing onto the Myd88-/- background that will enable us to determine involvement of MyD88-independent TLR signaling and MyD88- independent IL-12 in adaptive immunity to infection. Aim 2: Determine if inflammatory monocytes drive MyD88-independent protective immunity. We hypothesize that inflammatory monocytes, known for their microbicidal activity against T. gondii, are an unrecognized driver of MyD88-independent adaptive immunity. The hypothesis will be tested using in vivo mAb cell depletion and analysis of Myd88-/- IL-12-eYFP reporter mice that we will generate in this aim. The importance of the research is that we will generate data on uninvestigated MyD88-independent pathways driving adaptive immunity. This is likely to have an impact on understanding human immunity since populations deficient in MyD88 retain resistance to all but a narrow range of infections. Accordingly, the practical significance of this project is that we expect to identify new targets fr vaccine development and for immunotherapy during infection and inflammation.