CNS Tuberculosis

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。

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.