The Role of Interleukin-10 During Fatal Alphavirus Encephalomyelitis

IL-10 在致命甲病毒脑脊髓炎中的作用

• 批准号: 8461728
• 负责人: Kirsten Kulcsar
• 金额: $ 4.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461728
• 关键词: Abbreviations; Adult; Affect; Age; Alphavirus; Americas; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Arboviruses; Area; C57BL/6 Mouse; Cause of Death; Cell Death; Cells; Cessation of life; Complex; Disease; Disease Outbreaks; Encephalitis; Encephalomyelitis; Fatal Outcome; Figs - dietary; Glutamates; Goals; Human; Immune; Immune response; Immune system; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-17; Knockout Mice; Limb structure; Lymphoid; MHC Class II Genes; Mediating; Microglia; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Neuraxis; Neurons; Neuroprotective Agents; Onset of illness; Paralysed; Pathogenesis; Pathology; Pharmaceutical Preparations; Pharmacologic Substance; Play; Predisposition; Production; Regulation; Reporter; Research; Role; Sindbis Virus; Source; Stress; Study models; T-Cell Activation; T-Lymphocyte; Therapeutic Intervention; Tropism; Viral; Viral Encephalitis; Virulence; Virulent; Virus; Virus Diseases; Western Equine Encephalitis Virus; Wild Type Mouse; age related; arm; base; chemokine; cytokine; effective intervention; excitotoxicity; immune activation; immunodeficient mouse model; immunopathology; in vivo; interleukin-23; mRNA Expression; macrophage; mortality; neuron apoptosis; neuron loss; neurotoxic; neurotropic virus; prevent; therapeutic development; vector

DESCRIPTION (provided by applicant): Encephalitic arthropod-borne viruses are emerging as a major cause of death and disease worldwide. Understanding the mechanisms involved in severe and fatal encephalitic infections is critical in developing effective interventions. Sindbis virus (SV), the prototypic alphavirus, is related to Venezuelan, eastern, and western equine encephalitis viruses, which cause seasonal outbreaks of encephalitis in the Americas. SV causes mild disease in humans, but has a neuronal tropism and causes encephalomyelitis in mice. The virulence of SV is age-dependent and virus-strain dependent. Neuroadapted Sindbis virus (NSV) is a virulent strain of SV that causes fatal encephalomyelitis in mice of all ages. Viral clearance correlates with the onset of paralysis suggesting that the immune response is causing pathology, not viral replication. Inhibition of the immune response by treating with pharmaceuticals or by using immunodeficient mouse models leads to protection during infection, further supporting the notion of immunopathology. Glutamate excitotoxicity is also implicated in fatal disease. Interleukin-10 (IL-10) is an anti-inflammatory molecule and a key regulator of both the innate and adaptive arms of the immune response. Its classic effects are to reduce T cell activation by inhibiting expression of MHC class II and co-stimulatory molecules. This dampens the immune response by reducing the production of pro-inflammatory cytokines and chemokines. IL-10 can also directly protect neurons from apoptosis in models of glutamate excitotoxicity and other stress conditions. The proposed research is aimed at determining the role IL-10 has in the central nervous system during fatal viral encephalitis. First, the critical source of IL-10 in the central nervous system (CNS) mediating mortality during NSV infection will be determined. IL-10 reporter mice will be used to evaluate which cells are producing IL-10 in the CNS. The source of IL-10 necessary for mediating protection will be determined by using mice that are deficient in either myeloid- or lymphoid-derived IL-10. Second, the role of IL-10 on regulating TH17 mediated immunopathology will be examined. IL-10 deficient (IL-10 -/-) mice will be used to determine the extent of inflammation and production of neurotoxic cytokines that occurs without IL-10 regulation. The amount of TH17 infiltrates and its products, IL-17, IL-23, and IL-21, will be quantified and survival in the absence of IL-10 and TH17 cells will be determined. Third, the role of IL-10 as a neuroprotective agent will be determined by exogenous administration to infected areas using NSV as a vector for IL-10 (dsNSV:IL-10) and evaluating its effects on morbidity and survival in IL-10 -/- and wild-type mice, determining its effects on neuronal apoptosis in vitro and in vivo, and examining its role in glutamate excitotoxicity. Determining the role of IL-10 in mediating fatal viral encephalomyelitis pathology will increase our understanding of the mechanisms responsible for severe and fatal infections and provide a basis for therapeutic development.

描述（由申请人提供）：脑炎节肢动物传播的病毒正在成为全世界死亡和疾病的主要原因。了解严重和致命性脑炎感染的机制对于制定有效的干预措施至关重要。辛德比斯病毒 (SV) 是一种原型甲病毒，与委内瑞拉、东部和西部马脑炎病毒有关，这些病毒导致美洲季节性脑炎爆发。 SV 在人类中引起轻微疾病，但具有神经元趋向性并在小鼠中引起脑脊髓炎。 SV 的毒力依赖于年龄和病毒株。神经适应性辛德比斯病毒 (NSV) 是一种强毒株，可导致所有年龄段的小鼠出现致命性脑脊髓炎。病毒清除与麻痹的发生相关，表明免疫反应引起病理，而不是病毒复制。通过药物治疗或使用免疫缺陷小鼠模型抑制免疫反应可以在感染期间提供保护，进一步支持了免疫病理学的概念。谷氨酸兴奋性毒性也与致命疾病有关。白介素 10 (IL-10) 是一种抗炎分子，也是先天性和适应性免疫反应的关键调节剂。其经典作用是通过抑制 MHC II 类和共刺激分子的表达来减少 T 细胞活化。这通过减少促炎细胞因子和趋化因子的产生来抑制免疫反应。在谷氨酸兴奋性毒性和其他应激条件模型中，IL-10 还可以直接保护神经元免于凋亡。拟议的研究旨在确定 IL-10 在致命病毒性脑炎期间在中枢神经系统中的作用。首先，将确定中枢神经系统 (CNS) 中介导 NSV 感染期间死亡的 IL-10 的关键来源。 IL-10 报告小鼠将用于评估中枢神经系统中哪些细胞产生 IL-10。介导保护所需的 IL-10 来源将通过使用缺乏骨髓或淋巴源性 IL-10 的小鼠来确定。其次，将检查 IL-10 在调节 TH17 介导的免疫病理学中的作用。 IL-10 缺陷 (IL-10 -/-) 小鼠将用于确定在没有 IL-10 调节的情况下发生的炎症程度和神经毒性细胞因子的产生。将定量 TH17 渗透物及其产物 IL-17、IL-23 和 IL-21 的量，并确定在不存在 IL-10 和 TH17 细胞的情况下的存活率。第三，IL-10作为神经保护剂的作用将通过使用NSV作为IL-10载体（dsNSV：IL-10）对感染区域进行外源性施用来确定，并评估其对IL-10-/-和野生型小鼠的发病率和存活率的影响，确定其在体外和体内对神经元凋亡的影响，并检查其在谷氨酸中的作用 兴奋性毒性。确定 IL-10 在介导致命性病毒性脑脊髓炎病理学中的作用将增加我们对严重和致命性感染机制的理解，并为治疗开发提供基础。