Murine coronavirus neurovirulence: role of type I interferon response

鼠冠状病毒神经毒力：I 型干扰素反应的作用

• 批准号: 8536418
• 负责人: Susan R Weiss
• 金额: $ 33.29万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8536418
• 关键词: 2-5A Synthetase; Ablation; Acute; Acute Disease; Animals; Antiviral Agents; Antiviral Response; Biological Models; Brain; Cells; Central Nervous System Diseases; Central Nervous System Infections; Central Nervous System Viral Diseases; Cessation of life; Chromosome Mapping; Chronic; Chronic Disease; Collection; Coronavirus; Coronavirus Infections; Demyelinating Diseases; Development; Effectiveness; Encephalitis; Equilibrium; Exhibits; Genes; Genetic; Genome; Hepatitis C; Histocompatibility Testing; Human; IFNAR1 gene; Immune; Immune response; Infection; Inflammatory; Integration Host Factors; Interferon Type I; Interferons; Intervention; Investigation; Knock-out; Life; Ligase; Liver; Maps; Microglia; Multiple Sclerosis; Murine hepatitis virus; Mus; Mutation; Neuraxis; Neuroectodermal Cell; Neuroglia; Neurons; Organ; Pathology; Pathway interactions; Peripheral; Proteins; Reporting; Resistance; Ribonucleases; Role; Signal Transduction; Study models; Testing; Therapeutic; Time; Tissues; Tropism; Viral; Viral Genes; Viral Pathogenesis; Viral hepatitis; Virulence; Virulence Factors; Virulent; Virus; Virus Diseases; Virus Replication; Wild Type Mouse; base; cell type; chronic demyelination; design; in vivo; interferon therapy; macrophage; mouse model; mutant; neurotropic virus; neurovirulence; novel; oligoadenylate; phosphoric diester hydrolase; positional cloning; receptor expression; response; type I interferon receptor; viral detection; virus host interaction

DESCRIPTION (provided by applicant): Viral infections of the central nervous system (CNS) can cause both acute and chronic diseases that devastate the host. This proposal aims to investigate the extent and effectiveness of the host's type I interferon (IFN) response in restricting virus replication and spread in the CNS, and in addition, the mechanisms used by viruses to antagonize the IFN response. Infection of mice with the murine coronavirus, mouse hepatitis virus (MHV), offers a convenient and compelling model for studying virus-induced encephalitis and chronic demyelinating diseases such as multiple sclerosis (MS). Using a collection of viral strains and mutants that display different tropisms and virulence levels, we showed previously that the extent of MHV neurovirulence depends on a combination of viral and host factors, including the type I IFN response (primarily IFN-¿/¿), an early and crucial response to viral invasion. MHV infects several CNS cell types, including neurons and glial cells, cells types that have been reported to express interferon-stimulated genes (ISGs) during infection of the CNS with multiple viruses. However, the basal expression level of these ISGs, crucial for detection of viral invasion and antiviral response, is lower in the brain compared with other organs. Consequently, the CNS may be less prepared to quickly respond to viral invasion. Also contributing to the virus-host interactions, MHV encodes multiple type I IFN antagonists, most notably the ns2 protein that confers antagonism of the potent antiviral 2',5'-oligoadenylate synthetase-ribonuclease L (OAS-RNaseL) pathway that is induced by IFN. In addition the highly neurovirulent JHM.WU strain antagonizes IFN- ¿/¿ induction. Based on these findings, we propose to use the mildly neurovirulent A59 strain as well as JHM.WU to test the following overall hypothesis: IFN- ¿/¿ signaling in the CNS can effectively restrict neurovirulent MHV spread in vivo. At the same time MHV has the ability to compromise the type I IFN response through cell-type specific IFN antagonism. The virus-host balance will depend on the tissue and cell types infected and virus strain-specific proteins that compromise the IFN-¿/¿ response. The following aims are proposed: 1) Determine the cell types that restrict neurovirulent MHV infection in the CNS in vivo, using A59 and JHM.WU along with mice deficient in type I IFN receptor expression, specifically in macrophage/microglia, neuroectodermal cells or neurons; 2) Investigate the effectiveness of the OAS-RNaseL pathway in limiting MHV induced pathology during acute and chronic CNS infection and 3) Map the genes and investigate the mechanisms underlying type I IFN antagonism and high neurovirulence of JHM.WU. Understanding the immune mechanisms and the CNS cell types that limit viral pathogenesis and characterizing the strategies used by neurovirulent MHV to evade the host type I IFN response will likely aid in the development of better therapeutics to treat virus-induced encephalitis in humans. Moreover, understanding type I IFN signaling in the CNS may aid in developing or refining therapeutic applications for type I IFNs, which are currently used in treatment of MS and hepatitis C.

描述（由申请人提供）：中枢神经系统（CNS）的病毒感染可引起对宿主造成毁灭性打击的急性和慢性疾病。本提案旨在研究宿主 I 型干扰素（IFN）反应在限制方面的程度和有效性。病毒在中枢神经系统中的复制和传播，此外，病毒用于拮抗鼠冠状病毒、小鼠肝炎病毒（MHV）感染小鼠的干扰素反应的机制，为研究提供了一种方便且有效的方法。研究病毒引起的脑炎和多发性硬化症等慢性脱髓鞘疾病的令人信服的模型使用表现出不同趋向性和毒力水平的病毒株和突变体的集合，我们之前表明，MHV 神经毒力的程度取决于以下因素的组合。病毒和宿主因素，包括 I 型 IFN 反应（主要是 IFN-¿/¿），这是对病毒入侵的早期关键反应，可感染多种 CNS 细胞类型，包括神经元和细胞。神经胶质细胞是多种病毒感染中枢神经系统期间表达干扰素刺激基因（ISG）的细胞类型，然而，这些对于检测病毒入侵和抗病毒反应至关重要的 ISG 的基础表达水平较低。与其他测试的器官相比，MHV 编码多种 I 型 IFN 拮抗剂，特别是大多数 ns2 蛋白，因此可能不太容易对病毒入侵做出快速反应。拮抗 IFN 诱导的强效抗病毒 2',5'-寡腺苷酸合成酶 - 核糖核酸酶 L (OAS-RNaseL) 途径。此外，神经毒力 JHM.WU 菌株高度拮抗 IFN-¿ /¿基于这些发现，我们建议使用轻度神经毒性 A59 菌株以及 JHM.WU 来检验以下总体假设：IFN-¿ /¿中枢神经系统中的信号传导可以有效限制神经毒性 MHV 在体内的传播，同时 MHV 具有通过细胞类型特异性 IFN 拮抗作用来损害 I 型 IFN 反应的能力。病毒-宿主平衡将取决于感染的组织和细胞类型。以及损害 IFN-¿ 的病毒株特异性蛋白质/¿提出以下目标： 1) 使用 A59 和 JHM.WU 以及 I 型 IFN 受体表达缺陷的小鼠，特别是巨噬细胞/小胶质细胞、神经外胚层细胞，确定限制 CNS 体内神经毒性 MHV 感染的细胞类型。或神经元；2) 研究 OAS-RNaseL 通路在限制急性和慢性 CNS 感染期间 MHV 诱导的病理学方面的有效性，以及 3) 绘制基因图谱并研究潜在类型的机制JHM.WU 的 I IFN 拮抗作用和高神经毒力。了解限制病毒发病机制的免疫机制和 CNS 细胞类型，并描述神经毒力 MHV 用来逃避宿主 I 型 IFN 反应的策略，可能有助于开发更好的治疗方法。此外，了解中枢神经系统中的 I 型干扰素信号传导可能有助于开发或完善目前用于治疗多发性硬化症的 I 型干扰素的治疗应用。和丙型肝炎。