CNS Tuberculosis

中枢神经系统结核

• 批准号: 8373013
• 负责人: Zsuzsanna Fabry
• 金额: $ 32.92万
• 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/8373013
• 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. PUBLIC HEALTH RELEVANCE: Despite the availability of effective short-course chemotherapy and the Bacille Calmette- Guerin (BCG) vaccine, the tubercle bacillus continues to claim more lives than any other single infectious agent. Recent years have demonstrated an increased incidence of tuberculosis in both developing and industrialized countries, the widespread emergence of drug-resistant strains and a deadly synergy with the human immunodeficiency virus (HIV). IN 1993, the World Health Organization (WHO) declared a tuberculosis (TB) global emergency and it is estimated that today 1/3, approximately 2 billion people, of the global population is infected with latent TB. CNS tuberculosis (CNSTB) is the most dangerous form of Mtb infection. The diagnosis is challenging, and the disease is clinically hard to manage. Mortality, even with rigorous treatment, is high, and of those who survive ~27% develop severe neurological damage and disability. Despite the severity of this disease, current understanding about the pathogenesis of CNSTB is still dated back to necropsy data published in 1933. Treatment has advanced little since the introduction of isoniazid in the 1950s (Clin Chest Med 30(4): 745-754). Therapeutic approaches are limited to chemotherapy developed over 30 years ago, and the lack of progress in research on pathogenesis has put the development of new treatments on hold for decades. With drug-resistant strains emerging there is an urgent need for development of new strategies for therapeutic intervention and prevention of this disease. This project will provide new knowledge regarding pathogenesis of CNS tuberculosis and enable the development of preventive and therapeutic strategies to cope with this disease.

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，今天世界人口的三分之一，或约20亿人，感染了潜伏性结核病。最危险的结核分枝杆菌（Mtb）感染形式是中枢神经系统结核（CNSTB）。尽管其具有重要的公共卫生意义，但目前对CNSTB发病机制的了解非常有限，并且CNSTB患者的预后黯淡。CNSTB主要影响儿童和免疫缺陷成人。我们建立了新的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传递到CNS并促进Mtb在CNSTB中的传播。在我们的初步数据中，我们已经表明dc优先携带Mtb进入7日龄免疫缺陷小鼠的中枢神经系统。我们已经生成了表达绿色荧光蛋白（GFP）的新型重组结核分枝杆菌菌株，并创建了表达OVA257-264和OVA323-339抗原表位的结核分枝杆菌菌株。我们已经证明，这些新的结核分枝杆菌菌株可以在体内追踪，并用于检测CNSTB的全身适应性免疫。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Aim 1中，我们将确定DC在结核分枝杆菌传播到中枢神经系统（Aim 1A）中的作用，并研究血脑屏障（BBB）调节结核分枝杆菌感染的DC迁移（Aim 1B）的方式。在第二部分，我们将研究CNSTB的免疫控制。我们将利用我们对外周组织分枝杆菌控制的知识，确定哪些中枢神经系统和免疫细胞控制CNSTB中的分枝杆菌生长（Aim 2A）。使用Ag85、OT-I或OT-II转基因小鼠系以及表达这些表位的重组Mtb菌株，我们将剖析CNSTB （Aim 2B）中抗原特异性免疫反应的机制。在这些研究的结论中，我们将增加我们对CNSTB发病机制的了解，评估新的CNSTB体内模型，创建可用于跟踪Mtb体内感染的新试剂，并阐明血脑屏障在Mtb向中枢神经系统传播中的作用。这些实验将填补我们在CNSTB发病机制方面的知识空白，并将导致改进治疗中枢神经系统分枝杆菌感染的策略。