Mechanisms of Neuroinflammation in Experimental Cerebal Malaria

实验性脑型疟疾的神经炎症机制

• 批准号: 10674093
• 负责人: Robin Stephens
• 金额: $ 30.89万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10674093
• 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; Collaborations; Coma; 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; Mutant Strains Mice; Mutation; Neuroglia; Neurologic; Optics; Outcome; Parasites; Pathogenesis; Pathogenicity; Pathology; Patients; Persons; 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; Visualization; axon injury; brain parenchyma; cerebrovascular; 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.

项目摘要/摘要 恶性疟原虫感染的最坏结果是脑疟疾（CM）死亡。一个 估计每年有445,000人（大部分是儿童）死于CM，幸存者经常经历长期的长期 术语神经后遗症。宿主对感染的反应会导致脑病。但是， 病理学原因是多因素，且不明确的原因，限制了治疗策略的发展 患者并降低死亡率。严重的血管充血，凝结和炎症增加 细胞因子每种因子与CM结局差相关。促进低水平调节的突变 IL-10细胞因子响应于寄生虫，与更严重的疾病相关，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理，但要具有挑战性 通过实验分开它们。因此，我们采用了高炎性实验CM的模型 （ECM），这是由于通常没有发现在大脑中隔离的非肺寄生虫菌株， 然而，在高炎环境（IL-10 KO）中引起了CM的许多症状。这个模型，在 与抗凝剂结合使用，将使我们能够检查炎症细胞因子和 以还原的方式凝血。在初步数据中，我们发现超炎驱动器 脑脉管系统中血栓形成，其中包含炎症白细胞。此外， 活化的神经胶质被吸引到这些血栓形成位点，表明炎症细胞因子扩增 内部或与这些血管焦点相关联。令人惊讶的是，用抗凝剂治疗导致 ECM的死亡率降低，以及降低的神经胶质和行为症状。因此，我们 假设与血栓相关的事件促进了细胞因子的扩增和神经病理学，要么是 捕获纤维蛋白（OGEN）在脉管系统中相互作用或通过直接激活胶质激活相互作用的免疫细胞 从血栓形成部位泄漏。我们将确定与血栓相关的机制 通过以下特定目的神经病理学：1）确定血栓的致病作用 高炎性实验性脑疟疾中血管内事件的炎症细胞，2） 确定疟疾感染中纤维蛋白原驱动的神经病理学的机制。这项研究将剖析 纤维蛋白（OGEN）有助于炎症和 脑疟疾的神经病理学。了解炎症与 ECM中促进神经病理学的凝血将推动鉴定涉及的关键因素 脑病理学导致未来潜在的治疗策略。这三个合作 调查人员带来了一个具有免费知识和技能的凝聚力团队：疟疾免疫学，， 大脑的神经免疫学和尖端成像，将其用于这个多学科项目，该项目将 提高我们对这种致命多因素疾病的理解。