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）全球紧急状态，据估计，今天世界人口的1/3，即约20亿人感染了潜伏性TB。最危险的结核分枝杆菌（Mtb）感染形式是中枢神经系统（CNS）结核病（CNSTB）。尽管它的公共卫生的重要性，目前的了解CNSTB的发病机制是非常有限的，与CNSTB患者的预后是暗淡的。CNSTB主要影响儿童和免疫缺陷成人。我们已经建立了新的MHC II类缺陷或RAG免疫缺陷小鼠模型来研究Mtb在CNS中的传播。我们假设树突状细胞（DC）提供Mtb进入CNS，并有助于Mtb传播CNSTB。在我们的初步数据中，我们已经表明，在7日龄免疫缺陷小鼠中，DC优先将Mtb携带到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OVA 257 -264和OVA 323 -339抗原表位的Mtb菌株。我们已经表明，这些新的Mtb菌株可以在体内跟踪，并用于测试CNSTB的系统适应性免疫。我们的总体目标是确定Mtb传播到CNS的机制。在目标1中，我们将确定DC在Mtb向CNS传播中的作用（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）。目的二是研究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）。使用确定的转Ag 85、OT-I或OT-II基因的小鼠品系，以及表达这些表位的重组Mtb菌株，我们将剖析CNSTB中抗原特异性免疫应答的机制（Aim 2B）。在这些研究的结论，我们将增加我们的知识CNSTB发病机制，评估新的体内模型CNSTB，创造新的试剂，可用于跟踪结核分枝杆菌感染在体内，并阐明血脑屏障中的作用结核分枝杆菌传播到中枢神经系统。这些实验将填补我们对CNSTB发病机制的认识的差距，并将导致改善治疗CNS分枝杆菌感染的策略。 公共卫生关系：尽管有了有效的短程化疗和卡介苗，结核杆菌仍然比任何其他单一的传染性病原体夺去更多的生命。近年来，发展中国家和工业化国家的结核病发病率都有所增加，抗药性菌株的广泛出现以及与人体免疫缺陷病毒（艾滋病毒）的致命协同作用。1993年，世界卫生组织（WHO）宣布结核病（TB）全球紧急状态，据估计，今天全球人口的1/3，约20亿人感染了潜伏性TB。CNS结核病（CNSTB）是Mtb感染的最危险形式。诊断是具有挑战性的，这种疾病在临床上很难管理。即使经过严格的治疗，死亡率也很高，存活者中约有27%发展为严重的神经损伤和残疾。尽管这种疾病的严重性，目前对CNSTB的发病机制的理解仍然可以追溯到1933年发表的尸检数据。自20世纪50年代引入异烟肼以来，治疗进展甚微（Clin Chest Med 30（4）：745-754）。治疗方法仅限于30多年前开发的化学疗法，并且在发病机制研究方面缺乏进展使新治疗方法的开发搁置了几十年。随着耐药菌株的出现，迫切需要开发用于治疗干预和预防该疾病的新策略。该项目将提供有关中枢神经系统结核病发病机制的新知识，并能够制定预防和治疗策略，以科普这种疾病。