Mechanisms of Neuroinflammation in Experimental Cerebal Malaria

实验性脑型疟疾的神经炎症机制

• 批准号: 10237349
• 负责人: Robin Stephens
• 金额: $ 37.39万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237349
• 关键词: 3-Dimensional; Adhesions; Animals; Antibody Therapy; Anticoagulants; Antigen Presentation; Autopsy; Behavioral Symptoms; Binding; Blood Coagulation Disorders; Blood Vessels; Brain; Brain Death; Brain Pathology; Brain imaging; CD4 Positive T Lymphocytes; Cells; Cerebral Malaria; Cerebrovascular system; Cerebrum; Cessation of life; Child; Coagulation Process; Coma; Congestive; Data; Development; Disease; Edema; Encephalopathies; Endothelial Cells; Endothelium; Etiology; Event; Extravasation; Fibrin; Fibrinogen; Flow Cytometry; Future; Genetic Polymorphism; Genome; Gliosis; Goals; Hemorrhage; Human; ITGAM gene; Image; Immune; Immune response; Immune system; Immunofluorescence Immunologic; Immunology; Infection; Inflammation; Inflammatory; Inflammatory Infiltrate; Inflammatory Response Pathway; Interferon Type II; Interleukin-1; Interleukin-10; Knowledge; Lead; Leukocytes; Low-Molecular-Weight Heparin; Malaria; Microglia; Microscopy; Modeling; Mus; Mutation; Neuroglia; Neurologic; Optics; Outcome; Parasites; Pathogenesis; Pathogenicity; Pathology; Patients; Plasmodium falciparum; Positioning Attribute; Production; Proteins; Reporter; Research Personnel; Risk; Role; Serum; Site; Survivors; Symptoms; T-Lymphocyte; TNF gene; Testing; Therapeutic; Thrombosis; Thrombus; Variant; Vascular Endothelium; axon injury; base; brain parenchyma; cerebrovascular; cohesion; cytokine; experience; fighting; improved; in vivo; intravital microscopy; malaria infection; monocyte; mortality; multidisciplinary; neuroimmunology; neuroinflammation; neuropathology; novel; prevent; response; skills; success; therapy development; thrombotic; tool

PROJECT SUMMARY/ABSTRACT The worst outcome of infection with Plasmodium falciparum is death from Cerebral Malaria (CM). An estimated 445,000 people, mostly children, die yearly from CM and survivors often experience long- term neurological sequelae. The host response to infection causes encephalopathy. However, the causes of pathology are multi-factorial, and not well-defined, limiting development of strategies to treat patients and reduce mortality. Severe vascular congestion, coagulation, and increased inflammatory cytokines each correlate with poor CM outcomes. Mutations that promote low levels of the regulatory cytokine, IL-10, in response to parasite correlate with more severe disease, as do low serum levels. While both parasite and host variation are likely to contribute to pathogenesis, it is challenging to separate them experimentally. Therefore, we employ a model of hyper-inflammatory experimental CM (eCM), which is due to a normally non-virulent parasite strain that is not found sequestered in the brain, and yet causes many of the symptoms of CM in a hyper-inflammatory setting (IL-10 KO). This model, in combination with anti-coagulants, will allow us to examine the role of inflammatory cytokines and coagulation in a reductionist manner. In preliminary data, we found that hyper-inflammation drives formation of thrombi in the brain vasculature that contain inflammatory leukocytes. Furthermore, activated glia are attracted to these thrombotic sites suggesting amplification of inflammatory cytokines within or associated with these vascular foci. Strikingly, treatment with anti-coagulant resulted in reduced mortality from eCM, as well as reduced gliosis and behavioral symptoms. Therefore, we hypothesize that thrombus-associated events promote cytokine amplification and neuropathology, either by trapping immune cells, which interact within the vasculature, or by direct activation of glia, by fibrin(ogen) leaked from the site of thrombosis. We will determine the mechanisms of thrombus-associated neuropathology through the following specific aims: 1) Determine the pathogenic effects of thrombi and inflammatory cells on intravascular events in hyperinflammatory experimental Cerebral Malaria and 2) Determine mechanisms of Fibrinogen-driven neuropathology in malaria infection. This study will dissect the complimentary and overlapping mechanisms by which fibrin(ogen) contributes to inflammation and neuropathology in cerebral malaria. Understanding the interactions between inflammation and coagulation promoting neuropathology in eCM will drive identification of critical factors involved in cerebral pathology leading to potential therapeutic strategies in the future. The three collaborating investigators bring a cohesive team with complimentary knowledge and skills: immunology of malaria, neuroimmunology and cutting-edge imaging of the brain, to this multi-disciplinary project which will improve our understanding of this lethal multi-factorial disease.

项目概要/摘要 感染恶性疟原虫最糟糕的结果是死于脑型疟疾（CM）。一个 据估计，每年有 445,000 人（其中大部分是儿童）死于 CM，幸存者经常经历长期的 术语“神经系统后遗症”。宿主对感染的反应导致脑病。然而， 病理原因是多因素的，且不明确，限制了治疗策略的制定 患者并降低死亡率。严重的血管充血、凝血和炎症增加 每种细胞因子都与不良的 CM 结局相关。促进低水平监管的突变 对寄生虫作出反应的细胞因子 IL-10 与更严重的疾病相关，血清水平低也是如此。 虽然寄生虫和宿主变异都可能导致发病机制，但要确定这一点具有挑战性。 通过实验将它们分开。因此，我们采用高炎症实验 CM 模型 (eCM)，这是由于一种通常无毒力的寄生虫菌株引起的，但未发现其存在于大脑中， 但在高炎症环境下会引起 CM 的许多症状 (IL-10 KO)。这个模型，在 与抗凝血剂结合，将使我们能够检查炎症细胞因子的作用和 以还原论方式进行凝结。在初步数据中，我们发现过度炎症会导致 在含有炎性白细胞的脑血管系统中形成血栓。此外， 活化的神经胶质细胞被吸引到这些血栓部位，表明炎症细胞因子的放大 在这些血管病灶内或与这些血管病灶相关。引人注目的是，使用抗凝剂治疗导致 降低了 eCM 的死亡率，并减少了神经胶质增生和行为症状。因此，我们 假设血栓相关事件通过以下方式促进细胞因子放大和神经病理学： 捕获在脉管系统内相互作用的免疫细胞，或通过纤维蛋白（原）直接激活神经胶质细胞 从血栓形成部位漏出。我们将确定血栓相关的机制 神经病理学通过以下具体目标：1）确定血栓和血栓的致病作用 炎症细胞对高炎症实验性脑疟疾血管内事件的影响和 2) 确定疟疾感染中纤维蛋白原驱动的神经病理学机制。本研究将剖析 纤维蛋白（原）导致炎症和炎症的互补和重叠机制 脑型疟疾的神经病理学。了解炎症与炎症之间的相互作用 eCM 中促进凝血的神经病理学将推动对参与的关键因素的识别 脑病理学导致未来潜在的治疗策略。三人合作 研究人员带来了一支具有互补知识和技能的有凝聚力的团队：疟疾免疫学， 神经免疫学和尖端的大脑成像，这个多学科项目将 提高我们对这种致命的多因素疾病的了解。