Basis of MyD88-independent Th1 immunity during Toxoplasma infection

 描述(由申请人提供) 这项建议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，弓形虫是一种触发强大的Th1免疫的病原体，通常使宿主存活和寄生虫包囊在中枢神经系统内。以前的工作已经确定Toll样受体(TLR)-MyD88信号通路参与驱动树突状细胞IL-12的产生，从而有助于激活保护性T细胞和控制感染。在这一建议中，中心假设是MyD88对弓形虫的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。缺乏MyD88的小鼠的初步数据表明，在接种减毒弓形虫疫苗后，出现了预置的T细胞和对感染的免疫力，这一点得到了支持。这一假设将通过两个具体目标进行检验。目的1：确定在缺乏MyD88的情况下，保护性免疫是否需要TLR/IL-12信号。通过基因杂交到MyD88-/-背景上，将产生一组基因敲除小鼠，这将使我们能够确定MyD88非依赖TLR信号和MyD88非依赖IL-12在感染获得性免疫中的参与。目的2：确定炎性单核细胞是否驱动MyD88非依赖性保护性免疫。我们假设炎性单核细胞是MyD88非依赖性获得性免疫的未知驱动因素，该细胞以对弓形虫的杀微生物活性而闻名。这一假说将通过体内单抗细胞耗尽和分析MyD88-/-IL-12-EYFP报告小鼠来验证，我们将为此目的而产生。这项研究的重要性在于，我们将产生有关驱动适应性免疫的未被研究的MyD88独立通路的数据。这可能会对理解人类免疫力产生影响，因为MyD88基因缺陷的人群对除少数感染之外的所有感染都保持着抵抗力。因此，该项目的实际意义在于，我们期望为疫苗开发和感染和炎症期间的免疫治疗确定新的靶点。

 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.