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The role of lymphatic clearance in brain TB

淋巴清除在脑结核中的作用

基本信息

批准号：
10522419
负责人：
Matyas Sandor
金额：
$ 40.69万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-15 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522419
关键词：
Affect Alzheimer&apos s Disease Anti-Bacterial Agents Antibacterial Response Antigens Autoimmune Diseases Bacterial Infections Binding Brain Brain Drains Brain Pathology Cell physiology Cells Central Nervous System Infections Central Nervous System Tuberculosis Cerebral Edema Cerebrospinal Fluid Cerebrum Cervical lymph node group Complex Data Dendritic Cells Disease Disease Outcome Disease model Dorsal Drainage procedure Dura Mater Edema Encephalitis Endothelial Cells Experimental Autoimmune Encephalomyelitis Foundations Granuloma Homeostasis Human ITGAX gene Immune Immune response Immunity Immunologic Surveillance Impaired cognition In Situ Infiltration Inflammation Inflammatory Inflammatory Response Intercellular Fluid Lead Lesion Liquid substance Longitudinal Studies Lung Lymphangiogenesis Lymphatic Lymphatic System Lymphatic clearance Lymphoid Mediating Meningeal Meninges Modeling Multiple Sclerosis Mus Mycobacterium Infections Nerve Degeneration Neuraxis Outcome Parkinson Disease Pathogenesis Pathogenicity Pathology Physiology Play Production Proteins Publishing Regulation Regulatory Pathway Reporting Research Resolution Role Route Sculpture Severities Source Structure of choroid plexus System T-Lymphocyte Testing Therapeutic Tissues Traumatic Brain Injury Tuberculosis Tyrosine Kinase Inhibitor VEGFC gene Vascular Endothelial Growth Factor Receptor-3 Waste Management autoimmune inflammation brain parenchyma cribriform plate immunoregulation interest lymph nodes lymphatic circulation lymphatic drainage lymphatic vessel macrophage mortality mouse model mycobacterial neuroinflammation nonhuman primate novel novel therapeutic intervention novel therapeutics response trafficking tuberculosis treatment uptake wasting

项目摘要

PROJECT SUMMARY/ABSTRACT Brain tuberculosis (TB), the most severe form of tuberculosis, is associated with a complex inflammatory response, tissue damage and cerebral edema. Typically, management of fluid, waste, and immune- surveillance in the periphery is performed by tissue infiltrating lymphoid vessels. While the brain parenchyma does not have lymphoid vessels, recent research has identified that brain fluids (cerebrospinal fluid and interstitial fluid) are collected by meningeal and cribriform lymphoid vessels surrounding the brain, which are crucial for waste clearance and tissue homeostasis in the CNS. It has been shown that inhibition of lymphatic transport accelerates disease pathology and cognitive decline in Alzheimer’s disease, traumatic brain injury, and Parkinson’s disease, but little is known about the potential modulatory role of lymphoid vessels in CNS tuberculosis. Recently we reported that autoimmune inflammation induces lymphangiogenesis at the cribriform plate through the production of VEGFC from inflammatory dendritic cells. Functionally, the induction of new lymphoid vessels upregulates immunoregulatory molecules, and blocking new lymphoid vessel formation has consequences in regulating the severity of the autoimmune disease. In this proposal, we will test how CNS tuberculosis affects meningeal and cribriform lymphoid vessels formation and consequently, their fluid and cell draining function (Aim 1) To understand the impacts on immune-surveillance, we will study how CNS mycobacterial tuberculosis (Mtb) infection alters the expression of immune regulatory molecules on draining lymphoid vessels and how these lymphoid vessels modify brain-derived dendritic cells and their ability to influence downstream T cell priming in the lymph node (Aim 2). Lastly, we will use agents that block or promote lymphangiogenesis to test how brain inflammation, bacterial load, dissemination, and anti-bacterial immunity are affected by alterations of brain drainage with the hope of decreasing CNSTB associated pathologies (Aim 3). CNS tuberculosis is one of the most common bacterial infections of the brain with high mortality with a pressing need for new therapies, and these studies will lead to novel therapeutic strategies in CNSTB. The objectives of this proposal are (1) to test whether infiltrating or resident immune cells produce VEGFC that contributes to cribriform plate-associated, dorsal meningeal, or basal meningeal lymphangiogenesis during central nervous system tuberculosis (CNSTB) (Aim 1); to define cellular and bacterial interaction between Mtb- infected dendritic cells, Mtb, and lymphoid endothelial cells (LECs) (Aim 2); and to understand the translational value of lymphangiogenesis regulators on CNSTB pathogenesis, bacterial control, anti-bacterial responses, and bacterial dissemination (Aim 3). These studies will lead to a new aspect of brain TB pathology and reveal novel information comparing lymphatic vessel responses and brain drainage in different brain inflammations. These studies' long- term objective is to define how the lymphatic system represents a novel target in combating CNSTB.

项目概要/摘要脑结核 (TB) 是最严重的结核病形式，与复杂的炎症有关反应、组织损伤和脑水肿。通常，液体、废物和免疫的管理外周的监测是通过组织浸润淋巴管进行的。虽然脑实质没有淋巴管，最近的研究发现脑液（脑脊液和间质液）由大脑周围的脑膜和筛状淋巴管收集，对于中枢神经系统的废物清除和组织稳态至关重要。研究表明，抑制淋巴管运输会加速阿尔茨海默病、创伤性脑损伤、和帕金森病，但人们对淋巴管在中枢神经系统中的潜在调节作用知之甚少结核。最近我们报道了自身免疫炎症诱导筛状淋巴管生成通过炎性树突状细胞产生 VEGFC 进行培养。从功能上讲，引入新的淋巴管上调免疫调节分子，并阻止新的淋巴管形成调节自身免疫性疾病严重程度的后果。在本提案中，我们将测试 CNS 如何结核病影响脑膜和筛状淋巴管的形成，从而影响其液体和细胞排水功能（目标 1）为了了解对免疫监视的影响，我们将研究如何中枢神经系统结核分枝杆菌（Mtb）感染改变免疫调节分子的表达引流淋巴管以及这些淋巴管如何改变脑源性树突状细胞及其能力影响淋巴结中下游 T 细胞的启动（目标 2）。最后，我们将使用阻止或促进淋巴管生成，以测试大脑炎症、细菌负荷、传播和抗菌的情况免疫力受到脑引流改变的影响，希望减少 CNSTB 相关的病理学（目标 3）。中枢神经系统结核是最常见的脑部细菌感染之一。迫切需要新疗法，这些研究将带来新的治疗策略 CNSTB。该提案的目标是 (1) 测试浸润或常驻免疫细胞是否产生 VEGFC 有助于筛板相关、背侧脑膜或基底脑膜淋巴管生成中枢神经系统结核病（CNSTB）（目标 1）；定义 Mtb- 之间的细胞和细菌相互作用受感染的树突状细胞、Mtb 和淋巴内皮细胞 (LEC)（目标 2）；并理解翻译淋巴管生成调节剂对 CNSTB 发病机制、细菌控制、抗菌反应的价值，和细菌传播（目标 3）。这些研究将带来脑结核病理学的新方面，并揭示比较的新信息不同脑部炎症中的淋巴管反应和脑引流。这些研究长期术语目标是定义淋巴系统如何成为对抗 CNSTB 的新目标。