CNS Tuberculosis

中枢神经系统结核

• 批准号: 8470735
• 负责人: Zsuzsanna Fabry
• 金额: $ 31.77万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8470735
• 关键词: Adult; Affect; Antigens; Autopsy; Bacillus (bacterium); Back; Blood - brain barrier anatomy; Cells; Central Nervous System Infections; Central Nervous System Tuberculosis; Chest; Child; Data; Dendritic Cells; Developed Countries; Developing Countries; Development; Diagnosis; Disease; Drug resistance; Emergency Situation; Epitopes; Goals; Granuloma; Green Fluorescent Proteins; Growth; HIV; Immune; Immune response; Immunodeficient Mouse; Incidence; Infectious Agent; Knowledge; Laboratories; Lead; MHC Class II Genes; Methods; Modeling; Mus; Mycobacterium Infections; Mycobacterium tuberculosis; Nervous System Trauma; Neuraxis; Pathogenesis; Patients; Peripheral; Population; Preventive; Process; Public Health; Publishing; Reagent; Recombinants; Research; Role; Route; Severity of illness; T-Cell Receptor; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Organisms; Tuberculosis; Vaccines; World Health Organization; adaptive immunity; cell motility; chemotherapy; coping; cytokine; disability; disorder prevention; immunodeficient mouse model; improved; in vivo; in vivo Model; innovation; isoniazid; mortality; mycobacterial; novel; outcome forecast; research study; resistant strain

DESCRIPTION (provided by applicant): The World Health Organization (WHO) declared a tuberculosis (TB) global emergency, and it is estimated that today 1/3 of the world population, or approximately 2 billion people, is infected with latent TB. The most dangerous form of Mycobacterium tuberculosis (Mtb) infection is central nervous system (CNS) tuberculosis (CNSTB). Despite its public health importance, current understanding about the pathogenesis of CNSTB is very limited, and prognosis for patients with CNSTB is bleak. CNSTB largely affects children and immunodeficient adults. We have established novel MHC class II- deficient or RAG immunodeficient mouse models to study Mtb dissemination in the CNS. We hypothesize that dendritic cells (DCs) deliver Mtb into the CNS and contribute to Mtb dissemination in CNSTB. In our preliminary data, we have shown that DCs preferentially carry Mtb into the CNS in 7-day-old immunodeficient mice. We have generated novel recombinant Mtb strains that express green fluorescent protein (GFP) and created Mtb strains that express OVA257-264 and OVA323-339 antigenic epitopes. We have shown that these novel Mtb strains can be tracked in vivo and utilized for testing systemic adaptive immunity in CNSTB. Our overall goal is to define the mechanisms of Mtb dissemination into the CNS. In Aim 1, we will determine the role of DCs in Mtb dissemination into the CNS (Aim 1A) and investigate the means by which the blood- brain barrier (BBB) regulates Mtb-infected DC migration (Aim 1B). In Aim 2, we will study immunological control of CNSTB. We will take advantage of our knowledge of mycobacterial control in peripheral tissues and define which CNS and immune cells control mycobacterial growth in CNSTB (Aim 2A). Using defined mouse lines transgenic for Ag85, OT-I, or OT-II, as well as recombinant Mtb strains expressing these epitopes, we will dissect the mechanism of antigen-specific immune response in CNSTB (Aim 2B). At the conclusion of these studies, we will have increased our knowledge of CNSTB pathogenesis, evaluated new in vivo models of CNSTB, created novel reagents that can be used to track Mtb infections in vivo, and elucidated the role of the BBB in Mtb dissemination into the CNS. These experiments will fill the gap in our knowledge regarding the pathogenesis of CNSTB and will lead to improved strategies for treating mycobacterial infections of the CNS.

描述（由申请人提供）：世界卫生组织 (WHO) 宣布全球结核病 (TB) 紧急状态，估计当今世界人口的 1/3，即大约 20 亿人感染了潜伏性结核病。结核分枝杆菌 (Mtb) 感染最危险的形式是中枢神经系统 (CNS) 结核 (CNSTB)。尽管 CNSTB 对公共卫生具有重要意义，但目前对 CNSTB 发病机制的了解非常有限，CNSTB 患者的预后也很黯淡。 CNSTB 主要影响儿童和免疫缺陷成人。我们建立了新型 MHC II 类缺陷或 RAG 免疫缺陷小鼠模型来研究 Mtb 在中枢神经系统中的传播。我们假设树突状细胞 (DC) 将 Mtb 递送至 CNS，并有助于 Mtb 在 CNSTB 中传播。在我们的初步数据中，我们发现 DC 优先将 Mtb 携带到 7 日龄免疫缺陷小鼠的 CNS 中。我们已经产生了表达绿色荧光蛋白 (GFP) 的新型重组 Mtb 菌株，并创建了表达 OVA257-264 和 OVA323-339 抗原表位的 Mtb 菌株。我们已经证明，这些新的 Mtb 菌株可以在体内追踪并用于测试 CNSTB 的系统适应性免疫。我们的总体目标是确定结核分枝杆菌传播到中枢神经系统的机制。在目标 1 中，我们将确定 DC 在 Mtb 传播到 CNS 中的作用（目标 1A），并研究血脑屏障（BBB）调节 Mtb 感染的 DC 迁移的方式（目标 1B）。在目标 2 中，我们将研究 CNSTB 的免疫控制。我们将利用我们在外周组织中控制分枝杆菌的知识，并确定哪些 CNS 和免疫细胞控制 CNSTB 中的分枝杆菌生长（目标 2A）。使用确定的 Ag85、OT-I 或 OT-II 转基因小鼠品系，以及表达这些表位的重组 Mtb 品系，我们将剖析 CNSTB 中抗原特异性免疫反应的机制（目标 2B）。在这些研究结束时，我们将增加对 CNSTB 发病机制的了解，评估 CNSTB 的新体内模型，创建可用于追踪体内 Mtb 感染的新型试剂，并阐明 BBB 在 Mtb 传播到 Mtb 中的作用。中枢神经系统。这些实验将填补我们关于 CNSTB 发病机制的知识空白，并将改进治疗中枢神经系统分枝杆菌感染的策略。