IFN-gamma production by microglia for prevention of toxoplasmic encephalitis

小胶质细胞产生 IFN-γ 用于预防弓形虫脑炎

• 批准号: 7545401
• 负责人: YASUHIRO SUZUKI
• 金额: $ 14.45万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-03 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7545401
• 关键词: Acquired Immunodeficiency Syndrome; Address; Antigen Presentation; Brain; Cell Adhesion Molecules; Cells; Chronic; Defense Mechanisms; Development; Disease; Disease Management; Encephalitis; Endothelial Cells; Goals; Growth; Host Defense; Host Defense Mechanism; Immune; Immune response; Immunity; Immunocompromised Host; Individual; Infection; Infiltration; Interferon Type II; Life; MHC Class I Genes; Mediator of activation protein; Microglia; Migration Assay; Modeling; Molecular; Mus; Neuroglia; Neurons; Numbers; Organ; Parasites; Personal Satisfaction; Play; Prevention; Production; Public Health; Purpose; Recruitment Activity; Role; Source; Staging; System; T-Cell Activation; T-Lymphocyte; Toxoplasma gondii; Toxoplasmosis; brain cell; cerebrovascular; chemokine; cytokine; design; disorder prevention; improved; in vivo; macrophage; novel; prevent; response

DESCRIPTION (provided by applicant): Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). To improve prevention and management of TE, it is important to understand the immunopathogenesis of the disease. The murine models of TE that we developed provide an excellent opportunity to critically analyze the mechanisms of host defense in the brain. It is well documented that T cells recruited into the brain are an essential source of IFN-3 for prevention of TE. However, it is not known how the host defense functions during the early stage of reactivation of infection before large numbers of T cells enter the brain. This early defense system could be crucial for limiting tachyzoite growth and initiating T cell immunity to prevent TE. We recently found that microglia, which are resident macrophages in the brain parenchyma, produce IFN-3 during the early stage of reactivation. Our studies also suggest that production of IFN-3 by brain-specific cells, in addition to T cells, is required for prevention of TE. Therefore, IFN-3 production by microglia appears to be a novel early defense mechanism essential for prevention of the disease. The specific aims in this proposal are designed to define the role of IFN-3 produced by microglia in inhibition of tachyzoites growth, induction of T cell immunity, and prevention of TE. In the first aim, we will examine the inhibitory effects of IFN-3 produced by microglia on tachyzoite proliferation in the brain after reactivation of infection using mice that have IFN-3 production only by microglia. The second aim is to determine if IFN-3 production by microglia induces expression of mediators that recruit T cells into the brain. We will examine whether IFN-3 production by microglia induces expression of chemokines in brain cells and adhesion molecules on cerebrovascular endothelial cells. We will then use in vivo T cell migration assays to determine whether IFN-3 production by microglia facilitates infiltration of immune T cells into the brain. The third aim is to determine if IFN-3 production by microglia induces expression of MHC molecules for activation of T cells in the brain. In the fourth aim, we will determine the requirement of IFN-3 production by microglia and T cells for prevention of TE. For this purpose, we will purify immune T cells from infected wild-type or IFN-3-deficient mice and transfer these T cells into infected mice that express IFN-3 only by microglia or lack expression of this cytokine. Host mice will be followed for development of TE. We will also examine the role of IFN-3-dependent mediators of T cell recruitment determined in Specific Aim 2 for prevention of TE. The studies in these four specific aims will provide novel and crucial information that allows us to understand how IFN-3-production by microglia enables the host defense system in the brain to prevent TE. PUBLIC HEALTH RELEVANCE Reactivation of chronic Toxoplasma gondii infection in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). The proposed studies are to analyze how brain cells (microglia) inhibit parasite growth and induce the immune responses to prevent TE. This information will contribute to better understanding of the immunopathogenesis of TE and to improved prevention and management of the disease.

描述（由申请人提供）：免疫功能低下个体的大脑中慢性弓形虫感染的重新激活导致威胁生命的毒质细胞性脑炎（TE）的发展。为了改善TE的预防和管理，了解该疾病的免疫发作很重要。我们开发的TE的鼠模型为批判性地分析大脑中宿主防御的机制提供了绝佳的机会。有充分的文献证明，募集到大脑的T细胞是预防TE的IFN-3的重要来源。但是，在大量T细胞进入大脑之前，在感染重新激活的早期阶段，宿主防御如何在感染的早期起作用。这种早期的防御系统对于限制tachyzoite的生长和启动T细胞免疫以防止TE至关重要。我们最近发现，在重新激活的早期阶段，小胶质细胞是脑实质中驻留的巨噬细胞。我们的研究还表明，除T细胞外，还需要通过大脑特异性细胞产生IFN-3才能预防TE。因此，小胶质细胞产生的IFN-3似乎是预防疾病必不可少的新型早期防御机制。该提案中的具体目的旨在定义小胶质细胞在抑制速二鼠生长，T细胞免疫诱导和预防TE的作用中产生的IFN-3的作用。在第一个目的中，我们将使用小鼠使用仅由小胶质细胞产生IFN-3产生的小鼠在感染重新激活后，研究小胶质细胞产生的IFN-3对大脑中速氮岩增殖的抑制作用。第二个目的是确定小胶质细胞产生的IFN-3是否会诱导将T细胞募集到大脑中的介体的表达。我们将检查小胶质细胞产生的IFN-3是否诱导脑细胞中趋化因子的表达以及脑血管内皮细胞上的粘附分子。然后，我们将使用体内T细胞迁移分析来确定小胶质细胞产生的IFN-3是否促进免疫T细胞浸润到大脑中。第三个目的是确定小胶质细胞产生的IFN-3是否诱导MHC分子的表达来激活大脑中T细胞。在第四个目标中，我们将确定小胶质细胞和T细胞产生IFN-3对预防TE的要求。为此，我们将从感染的野生型或IFN-3缺陷小鼠中纯化免疫T细胞，并将这些T细胞转移到仅通过小胶质细胞表达IFN-3或缺乏该细胞因子表达的感染小鼠中。将遵循宿主小鼠的发展。我们还将研究在预防TE的特定目标2中确定的T细胞募集的IFN-3依赖性介体的作用。这四个特定目标中的研究将提供新颖而关键的信息，使我们能够了解小胶质细胞产生的IFN-3生产如何使大脑中的宿主防御系统预防TE。公共卫生相关性重新激活了免疫功能低下的个体大脑中慢性弓形虫感染的重新激活，导致威胁生命的弓形虫性脑炎（TE）的发展。拟议的研究旨在分析脑细胞（小胶质细胞）如何抑制寄生虫的生长并诱导免疫反应以防止TE。该信息将有助于更好地理解TE的免疫发病发生，并改善对疾病的预防和管理。