Basis of MyD88-independent Th1 immunity during Toxoplasma infection

弓形虫感染期间不依赖 MyD88 的 Th1 免疫的基础

• 批准号: 9110482
• 负责人: ERIC Y DENKERS
• 金额: $ 22.71万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110482
• 关键词: Animals; Antibodies; Attention; Attenuated; Automobile Driving; Bone Marrow; CD8B1 gene; Cells; Data; Dendritic Cells; Disease; Employee Strikes; Generations; Genetic Crosses; Hand; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunotherapy; In Vitro; Infection; Infection Control; Inflammation; Inflammatory; Interleukin-12; Knock-out; Knockout Mice; Knowledge; Lead; Life; Macrophage Colony-Stimulating Factor; Mediating; Memory; Microbe; Mus; Natural Immunity; Neuraxis; Opportunistic Infections; Parasites; Pathway interactions; Population; Production; Public Health; Receptor Signaling; Reporter; Research; Resistance; Role; Series; Signal Pathway; Signal Transduction; Source; T cell response; T-Lymphocyte; Testing; Th1 Cells; Toll-like receptor 11; Toll-like receptors; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Vaccinated; Vaccination; Vaccine Design; Vaccines; Work; adaptive immunity; antimicrobial; base; biodefense; cell type; congenital infection; cytokine; immune activation; improved; in vivo; macrophage; microbial; microbicide; monocyte; mouse model; neutrophil; pathogen; profilin; public health relevance; receptor; tool; vaccine development

 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.

 描述（由申请人提供） 该提案的长期目标是了解先天免疫识别和对微生物感染的反应，以推动适应性免疫学的出现。该项目的重点是用原生动物的寄生虫弓形虫贡氏菌感染小鼠感染，该病原体触发了强大的TH1免疫学，通常可以在中枢神经系统内实现宿主的生存和寄生虫的内科。先前的工作已经建立了Toll样受体（TLR）-MYD88信号通路的参与，驱动树突状细胞IL-12产生，有助于激活受保护的T细胞并控制感染。在该提议中，中心假设是对弓形虫的独立识别是导致自适应免疫组织化学感染的重要替代途径。这是由缺乏MyD88的小鼠的初步数据支持的，该数据显示出尖头的T细胞的出现和免疫组织化学在毒to骨毒性衰减后感染。该假设将以两个具体目标进行检验。 AIM 1：确定在没有MYD88的情况下是否需要保护性免疫的TLR/IL-12信号传导。通过遗传交叉在MyD88 - / - 背景上，将创建一组敲除小鼠，这将使我们能够确定与MyD88独立的TLR信号传导和MyD88无独立的IL-12参与至自适应免疫以感染感染。 AIM 2：确定炎症单核细胞是否驱动非依赖MyD88的保护免疫组织化学。我们假设炎性单核细胞以其对巨霉菌的微生物活性而闻名，是MyD88独立的适应性免疫组织化学的未识别驱动因素。该假设将使用MyD88 - / - IL-12-EYFP记者小鼠的体内mAb细胞部署以及我们将在此目标中生成的分析进行检验。这项研究的重要性在于，我们将生成有关驱动适应性免疫组织化学的不投资的无依赖性途径的数据。这可能会对理解人类免疫组织化学有影响，因为MyD88中的人群保留了除狭窄的感染范围以外的所有人的抗性。彼此之间，该项目的实际意义在于，我们期望在感染和注射期间确定新靶标的FR疫苗开发以及免疫疗法。