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）：免疫功能低下个体大脑中慢性弓形虫感染的重新激活会导致危及生命的弓形虫脑炎（TE）的发展。为了改善 TE 的预防和管理，了解该疾病的免疫发病机制非常重要。我们开发的 TE 小鼠模型为批判性分析大脑中宿主防御机制提供了绝佳的机会。有充分证据表明，招募到大脑中的 T 细胞是预防 TE 的 IFN-3 的重要来源。然而，尚不清楚在大量 T 细胞进入大脑之前感染重新激活的早期阶段，宿主防御是如何发挥作用的。这种早期防御系统对于限制速殖子生长和启动 T 细胞免疫以预防 TE 至关重要。我们最近发现小胶质细胞是脑实质中常驻的巨噬细胞，在重新激活的早期阶段会产生 IFN-3。我们的研究还表明，除了 T 细胞之外，脑特异性细胞产生 IFN-3 也是预防 TE 所必需的。因此，小胶质细胞产生的 IFN-3 似乎是预防该疾病所必需的一种新型早期防御机制。该提案的具体目标是确定小胶质细胞产生的 IFN-3 在抑制速殖子生长、诱导 T 细胞免疫和预防 TE 中的作用。第一个目标是，我们将使用仅由小胶质细胞产生 IFN-3 的小鼠来检查感染再激活后，小胶质细胞产生的 IFN-3 对大脑中速殖子增殖的抑制作用。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 细胞招募到大脑中的介质的表达。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和脑血管内皮细胞上粘附分子的表达。然后，我们将使用体内 T 细胞迁移测定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 是否会诱导 MHC 分子的表达，从而激活大脑中的 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 的需求，以预防 TE。为此，我们将从受感染的野生型或 IFN-3 缺陷小鼠中纯化免疫 T 细胞，并将这些 T 细胞转移到仅由小胶质细胞表达 IFN-3 或缺乏该细胞因子表达的受感染小鼠中。将跟踪宿主小鼠的 TE 发育情况。我们还将研究特定目标 2 中确定的 IFN-3 依赖性 T 细胞募集介质在预防 TE 中的作用。这四个具体目标的研究将提供新颖且重要的信息，使我们能够了解小胶质细胞产生的 IFN-3 如何使大脑中的宿主防御系统预防 TE。公共卫生相关性免疫功能低下个体大脑中慢性弓形虫感染的重新激活会导致危及生命的弓形虫脑炎 (TE)。拟议的研究旨在分析脑细胞（小胶质细胞）如何抑制寄生虫生长并诱导免疫反应以预防 TE。这些信息将有助于更好地了解 TE 的免疫发病机制，并改善该疾病的预防和管理。