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: 8474853
• 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/8474853
• 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（由申请方提供）：脑炎节肢动物传播病毒正在成为全球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。辛德毕斯病毒（SV）是一种原型甲病毒，与委内瑞拉、东部和西部马脑炎病毒相关，后者在美洲引起脑炎的季节性暴发。SV在人类中引起轻度疾病，但具有神经元嗜性并在小鼠中引起脑脊髓炎。SV的毒力具有年龄依赖性和毒株依赖性。神经适应性辛德毕斯病毒（NSV）是SV的一种强毒株，其在所有年龄的小鼠中引起致命性脑脊髓炎。病毒清除与瘫痪的发生相关，这表明免疫反应导致病理，而不是病毒复制。通过药物治疗或通过使用免疫缺陷小鼠模型抑制免疫应答导致感染期间的保护，进一步支持免疫病理学的概念。谷氨酸兴奋性毒性也与致命性疾病有关。白细胞介素-10（IL-10）是一种抗炎分子，也是免疫应答的先天性和适应性两个方面的关键调节因子。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应答。IL-10还可以在谷氨酸兴奋性毒性模型和其他应激条件下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IL-10介导NSV感染期间死亡率的关键来源。IL-10报告小鼠将用于评价CNS中产生IL-10的细胞。介导保护所必需的IL-10的来源将通过使用缺乏髓源性或淋巴源性IL-10的小鼠来确定。其次，将检查IL-10在调节TH 17介导的免疫病理学中的作用。将使用IL-10缺陷（IL-10 -/-）小鼠来确定在没有IL-10调节的情况下发生的炎症和神经毒性细胞因子的产生的程度。将定量TH 17浸润及其产物IL-17、IL-23和IL-21的量，并测定在不存在IL-10和TH 17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的载体（dsNSV：IL-10）对感染区域进行外源性给药来确定，并评估其对IL-10 -/-和野生型小鼠中的发病率和存活率的影响，确定其对体外和体内神经元凋亡的影响，并检查其在谷氨酸兴奋性毒性中的作用。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。