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: 8419399
• 负责人: Susan R Weiss
• 金额: $ 34.51万
• 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/8419399
• 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. PUBLIC HEALTH RELEVANCE: Infections with neurovirulent viruses can induce encephalitis and sometimes cause chronic central nervous system (CNS) disease. The proposed studies, using murine coronavirus infection of its natural host as a model system, will contribute to the understanding of the virus-host interactions that underlie virus-induced CNS disease and in the longer term contribute to the design of therapeutic strategies. These studies will, in addition, contribute to the understanding of interferon-¿/¿ signaling in the CNS and potentially to the refinement of type I interferon therapies for viral infections and multiple sclerosis.

描述（由适用提供）：中枢神经系统（CNS）的病毒感染会导致急性和慢性疾病破坏宿主。该提案旨在研究宿主I型干扰素（IFN）反应在限制病毒复制和扩散中枢神经系统中的范围和有效性，此外，病毒用来拮抗IFN反应的机制。小鼠感染鼠冠状病毒，小鼠肝炎病毒（MHV），为研究病毒诱导的脑炎和慢性脱髓鞘性疾病（如多发性硬化症（MS））提供了方便而引人注目的模型。我们使用表现出不同的朝向主义和病毒水平的病毒菌株和突变体的集合，以前表明，MHV神经病毒的程度取决于病毒和宿主因子的组合，包括I型IFN反应（主要是IFN-ifn-®/¿），早期和对病毒入侵的早期和关键反应。 MHV感染了几种CNS细胞类型，包括神经元和神经胶质细胞，据报道在具有多种病毒的中枢神经系统感染期间，已据报道表达干扰刺激的基因（ISGS）。但是，与其他器官相比，大脑中这些ISG的基本表达水平，对于病毒侵袭和抗病毒反应至关重要。因此，中枢神经系统可能不太准备快速应对病毒侵袭。 MHV还促进了病毒宿主相互作用，编码了多种I类IFN拮抗剂，最著名的是赋予潜在抗病毒2'，5'- 5'-橄榄核酸合成酶核糖核酸酶L（OAS-RNASEL）l（OAS-RNASEL）途径的NS2蛋白。另外，高度神经病毒JHM.WU菌株会拮抗Ifn-»诱导。基于这些发现，我们建议使用轻度神经病毒剂A59菌株以及JHM.WU测试以下总体假设：中枢神经系统中的IFN-€ /¿同时，MHV具有通过细胞类型特异性IFN拮抗作用损害I型IFN响应的能力。病毒宿主的平衡将取决于损害IFN-€ /€反应的感染的组织和细胞类型和病毒菌株特异性蛋白。提出了以下目的：1）使用A59和JHM.WU以及在巨噬细胞/小胶质细胞，神经外科疾病细胞或神经元中，使用A59和JHM.WU确定限制了体内中枢神经系统MHV感染的细胞类型； 2）研究OAS-RNASEL途径在限制MHV诱导的急性和慢性中枢神经系统感染过程中的有效性，3）绘制基因并研究JHM.WU的I型IFN拮抗和高神经病毒的机制。了解限制病毒发病机理的免疫力学和CNS细胞类型，并表征神经病毒MHV逃避宿主I型IFN反应的策略，可能有助于开发更好的治疗剂来治疗人类病毒诱导的脑炎。此外，了解中枢神经系统中的I型IFN信号传导可能有助于开发或完善I型IFN的治疗应用，这些应用当前用于治疗MS和丙型肝炎。 公共卫生相关性：神经病毒感染会诱导脑炎，有时会引起慢性中枢神经系统（CNS）疾病。提出的研究将其自然宿主作为模型系统的鼠冠状病毒感染，将有助于理解病毒诱导的中枢神经系统疾病的病毒宿主相互作用，从而有助于治疗策略的设计。此外，这些研究将有助于理解中枢神经系统中的干扰素信号传导，并有可能有助于对病毒感染和多发性硬化症的I型干扰素疗法的完善。