The role of lymphatic clearance in brain TB

项目摘要/摘要 脑结核病(TB)是最严重的结核病形式，与复杂的炎症性疾病有关 反应、组织损伤和脑水肿。通常情况下，对液体、废物和免疫的管理- 周围的监测是通过组织浸润性淋巴血管进行的。而脑实质 没有淋巴血管，最近的研究发现脑液(脑脊液和 间质液)由脑膜和筛状淋巴血管围绕大脑收集，这些淋巴管 对中枢神经系统的废物清除和组织动态平衡至关重要。已有研究表明，对淋巴的抑制 运输加速阿尔茨海默病、创伤性脑损伤、 和帕金森病，但对淋巴血管在中枢神经系统中的潜在调节作用知之甚少 肺结核。最近，我们报道了自身免疫性炎症诱导筛状淋巴管生成。 平板通过炎性树突状细胞产生VEGFC。从功能上讲，新的 淋巴管上调免疫调节分子，阻断新淋巴管的形成 在调节自身免疫性疾病的严重程度方面的后果。在这个提案中，我们将测试CNS如何 结核病会影响脑膜和筛状淋巴管的形成，从而影响它们的液体和细胞 引流功能(目标1)为了了解免疫监视的影响，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 影响下游T细胞在淋巴结中的启动(目标2)。最后，我们将使用阻止或 促进淋巴管生成以测试脑部炎症、细菌负荷、传播和抗菌作用 脑引流改变影响免疫力有望降低CNSTB相关 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，具有较高的 死亡率与迫切需要新的治疗方法，这些研究将导致新的治疗策略 CNSTB。 这项建议的目的是(1)测试渗透或常驻免疫细胞是否产生VEGFC 这有助于筛板相关的、背侧脑膜或基础脑膜淋巴管的生成 中枢神经系统结核(CNSTB)(目标1)；定义结核分枝杆菌与细菌之间的细胞和细菌相互作用 感染的树突状细胞、MTB和淋巴内皮细胞(LECs)(目标2)；并了解翻译的 淋巴管生成调节剂在CNSTB发病机制、细菌控制、抗菌反应等方面的价值 和细菌传播(目标3)。 这些研究将引领脑结核病理的一个新方面，并揭示新的信息比较 不同脑炎性疾病的淋巴管反应和脑引流。这些研究的长期- 术语目标是定义淋巴系统如何代表对抗CNSTB的新靶点。

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.