Mechanisms of Neuroinflammation in Experimental Cerebal Malaria

项目总结/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，其中大部分是儿童，死于CM，幸存者往往经历长期的- 神经系统后遗症宿主对感染的反应导致脑病。但 病理学原因是多因素的，并且不明确，限制了治疗策略的发展。 患者，降低死亡率。严重的血管充血、凝血和炎症增加 细胞因子均与CM结果不佳相关。促进低水平的调节基因的突变 细胞因子IL-10应答寄生虫与更严重疾病相关，低血清水平也是如此。 虽然寄生虫和宿主变异都可能导致发病机制，但 通过实验将它们分开。因此，我们采用高炎症实验性CM模型， (eCM)，这是由于一种通常无毒的寄生虫菌株，没有发现隔离在大脑中， 但在高度炎症环境中引起CM的许多症状（IL-10 KO）。这一模式，在 与抗凝剂联合使用，将使我们能够检查炎症细胞因子的作用， 以还原论的方式凝聚。在初步数据中，我们发现过度炎症会驱动 在含有炎性白细胞的脑血管系统中形成血栓。此外，委员会认为， 激活的神经胶质细胞被吸引到这些血栓形成部位，表明炎性细胞因子的扩增 在这些血管病灶内或与这些血管病灶相关。引人注目的是，抗凝血剂治疗导致 降低eCM的死亡率，以及减少神经胶质增生和行为症状。所以我们 假设血栓相关事件促进细胞因子扩增和神经病理学， 捕获免疫细胞，在脉管系统内相互作用，或通过纤维蛋白（原）直接激活神经胶质， 从血栓形成的部位漏出我们将确定血栓相关的机制 通过以下特定目的进行神经病理学研究：1）确定血栓的致病作用， 炎症细胞对高炎症实验性脑型疟疾血管内事件的影响; 确定疟疾感染中纤维蛋白原驱动的神经病理学机制。这项研究将剖析 纤维蛋白（原）促进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 eCM中促凝神经病理学将推动识别参与 脑病理学导致潜在的治疗策略在未来。三人合作 研究人员带来了一个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，这个多学科的项目，将 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.