CNS Tuberculosis

中枢神经系统结核

• 批准号: 9042435
• 负责人: Zsuzsanna Fabry
• 金额: $ 38.85万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9042435
• 关键词: Adult; Affect; Antigens; Autopsy; Bacillus (bacterium); Back; Blood - brain barrier anatomy; Calmette-Guerin Bacillus; 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）宣布结核病（TB）全球紧急情况，据估计，今天的1/3人口（约20亿人口）感染了潜在的结核病。结核分枝杆菌（MTB）感染的最危险形式是中枢神经系统（CNS）结核病（CNSTB）。尽管公共健康的重要性，但目前对CNSTB发病机理的理解非常有限，CNSTB患者的预后却黯淡。 CNSTB在很大程度上影响儿童和免疫缺陷的成年人。我们已经建立了新型的MHC II类缺陷或破布免疫缺陷的小鼠模型，以研究中枢神经系统中的MTB传播。我们假设树突状细胞（DC）将MTB输送到CNS中，并有助于CNSTB中的MTB传播。在我们的初步数据中，我们已经表明，DC优先将MTB带入7天大的免疫缺陷小鼠中的中枢神经系统中。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。我们已经表明，可以在体内跟踪这些新型MTB菌株，并用于测试CNSTB中的全身自适应免疫。我们的总体目标是将MTB传播机制定义为中枢神经系统。在AIM 1中，我们将确定DC在MTB传播中CNS中的作用（AIM 1A），并研究血液脑屏障（BBB）调节MTB感染的DC迁移的手段（AIM 1B）。在AIM 2中，我们将研究CNSTB的免疫控制。我们将利用对周围组织中分枝杆菌控制的了解，并定义哪些CNS和免疫细胞控制CNSTB中的分枝杆菌生长（AIM 2A）。使用定义的小鼠系转基因，用于AG85，OT-I或OT-II，以及表达这些表位的重组MTB菌株，我们将剖析CNSTB中抗原特异性免疫反应的机制（AIM 2B）。在这些研究的结论结束时，我们将增加对CNSTB发病机理的了解，评估了CNSTB的新型CNSTB模型，创建了新型试剂，可用于跟踪体内MTB感染，并阐明了BBB在MTB传播中的作用。这些实验将填补我们关于CNSTB发病机理的知识的空白，并将导致改善治疗CNS的分枝杆菌感染的策略。