Mechanisms of Neuroinflammation in Experimental Cerebal Malaria

项目摘要/摘要 感染恶性疟原虫的最坏结果是死于脑型疟疾(CM)。一个 据估计，每年有445,000人死于CM，其中大部分是儿童，幸存者经常经历长期的 长期的神经后遗症。宿主对感染的反应会导致脑病。然而， 病理原因是多因素的，而且没有明确的定义，限制了治疗策略的发展 减少病人和降低死亡率。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心肌梗死结局相关。促进低水平监管的突变 细胞因子IL-10对寄生虫的反应与更严重的疾病相关，血清水平低也是如此。 虽然寄生虫和寄主变异都可能导致发病，但要做到这一点具有挑战性。 通过实验将它们分开。因此，我们采用了一种高炎性实验性CM模型 (ECM)，这是由于一种通常无毒的寄生虫菌株，在大脑中没有发现隔离的， 并在高度炎症的环境下(IL-10 KO)引起CM的许多症状。此型号，在 与抗凝剂相结合，将使我们能够检查炎性细胞因子和 以简化论的方式凝聚。在初步数据中，我们发现过度炎症驱动 在含有炎性白细胞的脑血管中形成血栓。此外， 活化的胶质细胞被吸引到这些血栓部位，提示炎症细胞因子的放大 血管内的在这些血管内或与之相关的引人注目的是，抗凝剂的治疗导致了 减少ECM的死亡率，以及减少胶质细胞增多症和行为症状。因此，我们 假设血栓相关事件促进细胞因子放大和神经病理，要么是通过 捕获免疫细胞，这些细胞在血管系统内相互作用，或通过纤维蛋白(原)直接激活胶质细胞 从血栓形成的地方泄漏出来。我们将确定血栓相关的机制 神经病理学通过以下特定目的：1)确定血栓的致病作用和 炎性细胞在实验性高炎性脑疟疾血管内事件中的作用 确定疟疾感染中纤维蛋白原驱动的神经病理机制。这项研究将剖析 纤维蛋白(原)促进炎症的互补和重叠的机制 脑型疟疾的神经病理学。了解炎症和炎症之间的相互作用 凝血促进ECM的神经病理将推动对参与的关键因素的识别 脑病理导致了未来潜在的治疗策略。三个通力合作 研究人员带来了一支有凝聚力的团队，拥有免费的知识和技能：疟疾免疫学， 神经免疫学和大脑的尖端成像，这将是一个多学科的项目 提高我们对这种致命的多因素疾病的理解。

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.