The role of lymphatic clearance in brain TB

淋巴清除在脑结核中的作用

• 批准号: 10617380
• 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
• 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/10617380
• 关键词: Acceleration; Affect; Alzheimer' s Disease; Anti-Bacterial Agents; Antibacterial Response; Antigens; Antimycobacterial Agents; Autoimmune Diseases; Bacterial Infections; Binding; Brain; Brain Drains; Brain Pathology; Cell Communication; Cell physiology; Cells; Central Nervous System; 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; Lesion; Liquid substance; Longitudinal Studies; Lung; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic clearance; Lymphoid; Macrophage; Mediating; Meningeal; Meninges; Modeling; Multiple Sclerosis; Mus; Mycobacterium Infections; Nerve Degeneration; 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 C; Vascular Endothelial Growth Factor Receptor-3; Waste Management; autoimmune inflammation; brain parenchyma; cribriform plate; immunoregulation; interest; lymph nodes; lymphatic circulation; lymphatic drainage; lymphatic vessel; mortality; mouse model; mycobacterial; neuroinflammation; nonhuman primate; novel; novel therapeutic intervention; novel therapeutics; response; trafficking; tuberculosis treatment; uptake; wasting

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.

项目总结/摘要 脑结核（TB）是结核病最严重的形式，与复杂的炎症性疾病有关。 反应，组织损伤和脑水肿。一般来说，液体，废物和免疫的管理- 通过组织浸润淋巴管进行外周的监视。而脑实质 没有淋巴管，最近的研究已经确定，脑液（脑脊液和 间质液）由脑周围的脑膜和筛状淋巴管收集， 对于CNS中的废物清除和组织稳态至关重要。已经表明，抑制淋巴 运输加速阿尔茨海默病，创伤性脑损伤， 和帕金森病，但对中枢神经系统中淋巴管的潜在调节作用知之甚少 结核最近，我们报道了自身免疫性炎症诱导淋巴管生成在筛状 通过从炎性树突状细胞产生VEGFC来培养。在功能上，新的 淋巴管上调免疫调节分子，阻断新的淋巴管形成， 在调节自身免疫性疾病的严重程度方面的后果。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，因此，它们的液体和细胞 引流功能（目标1）为了了解对免疫监视的影响，我们将研究如何 CNS结核分枝杆菌（Mtb）感染改变了免疫调节分子的表达， 引流淋巴管以及这些淋巴管如何修饰脑源性树突状细胞及其能力 以影响淋巴结中的下游T细胞引发（Aim 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 免疫力受到脑引流改变的影响，希望减少与CNSTB相关的 病理学（目标3）。中枢神经系统结核病是最常见的脑部细菌感染之一， 死亡率与迫切需要新的治疗，这些研究将导致新的治疗策略， CNSTB。 本提案的目的是（1）测试浸润或驻留免疫细胞是否产生VEGFC 有助于筛板相关的，背侧脑膜，或基底脑膜淋巴管生成， 中枢神经系统结核病（CNSTB）（目的1）;确定Mtb- 感染的树突状细胞、结核分枝杆菌和淋巴样内皮细胞（LEC）（目的2）;并了解其翻译 淋巴管生成调节剂对CNSTB发病机制、细菌控制、抗菌反应 和细菌传播（目标3）。 这些研究将导致脑结核病病理学的一个新的方面，并揭示新的信息比较 淋巴管反应和脑引流在不同的脑炎症。这些研究长期以来- 术语目标是定义淋巴系统如何代表对抗CNSTB的新靶点。