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。该提案旨在研究宿主 I 型干扰素 (IFN) 反应在限制病毒在中枢神经系统中复制和传播方面的程度和有效性，以及病毒拮抗 IFN 反应的机制。小鼠感染鼠冠状病毒、小鼠肝炎病毒（MHV），为研究病毒引起的脑炎和多发性硬化症（MS）等慢性脱髓鞘疾病提供了一个方便且令人信服的模型。通过使用一系列表现出不同向性和毒力水平的病毒株和突变体，我们之前表明，MHV 神经毒力的程度取决于病毒和宿主因素的组合，包括 I 型 IFN 反应（主要是 IFN-¿/¿），这是对病毒入侵的早期且关键的反应。 MHV 感染多种中枢神经系统细胞类型，包括神经元和神经胶质细胞，据报道这些细胞类型在多种病毒感染中枢神经系统期间表达干扰素刺激基因 (ISG)。然而，与其他器官相比，这些对于检测病毒入侵和抗病毒反应至关重要的 ISG 的基础表达水平在大脑中较低。因此，中枢神经系统可能无法对病毒入侵做出快速反应。 MHV 编码多种 I 型 IFN 拮抗剂，也有助于病毒与宿主的相互作用，尤其是 ns2 蛋白，它可以拮抗 IFN 诱导的有效抗病毒 2',5'-寡腺苷酸合成酶 - 核糖核酸酶 L (OAS-RNaseL) 途径。此外，高神经毒力的 JHM.WU 菌株还能拮抗 IFN- ¿/¿ 的诱导。基于这些发现，我们建议使用轻度神经毒力A59毒株以及JHM.WU来检验以下总体假设：CNS中的IFN-¿/¿信号传导可以有效限制神经毒力MHV在体内的传播。同时，MHV 能够通过细胞类型特异性 IFN 拮抗作用来损害 I 型 IFN 反应。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-¿/¿ 反应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、神经外胚层细胞或神经元，确定限制 CNS 体内神经毒性 MHV 感染的细胞类型； 2) 研究 OAS-RNaseL 通路在急性和慢性 CNS 感染期间限制 MHV 诱导病理学的有效性，以及 3) 绘制基因图谱并研究 JHM.WU 的 I 型 IFN 拮抗和高神经毒力的机制。了解限制病毒发病机制的免疫机制和中枢神经系统细胞类型，并描述神经毒性 MHV 用于逃避宿主 I 型 IFN 反应的策略，可能有助于开发更好的疗法来治疗人类病毒引起的脑炎。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 I 型干扰素的治疗应用，目前 I 型干扰素用于治疗多发性硬化症和丙型肝炎。