The Cellular Stress Response in Viral Encephalitis

病毒性脑炎的细胞应激反应

基本信息

批准号：
7260329
负责人：
Michael J Oglesbee
金额：
$ 22.53万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-07-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7260329
关键词：
Address Adopted Affinity Amino Acid Substitution Amino Acids Animals Attenuated Vaccines Behavior Binding Binding Sites Biological Biological Assay Boxing Brain Canine Distemper Virus Canis familiaris Cells Cellular Stress Response Characteristics Complex Cultured Cells DNA Viruses Data Distemper Elevation Exhibits Family Fever Funding Gene Expression Genetic Transcription Genome Genomics Genotype Haplotypes Heat shock proteins Immune response Inbred BALB C Mice Infection Laboratories Life Cycle Stages Link Measles Measles virus Mediating Modeling Molecular Chaperones Molecular Conformation Mononegavirales Morbillivirus Mouse Strains Mus Neurologic Neurons Nucleocapsid Nucleocapsid Proteins Nucleosome Core Particle Numbers Outcome Paramyxovirus Patients Physiological Polymerase Predisposition Protein Overexpression Proteins Public Health RNA RNA Viruses Rabies Recombinants Research Personnel Resistance Retroviridae Role Side Stimulus Structure Structure-Activity Relationship Surface System T-Lymphocyte Tail Testing Therapeutic Intervention Time Vaccines Variant Viral Viral Antigens Viral Encephalitis Viral Proteins Virus Virus Diseases Work base borna virus cell mediated immune response cofactor design in vivo innovation mouse model neurotropic neurovirulence particle programs protein expression protein function response virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Cellular heat shock proteins (HSPs) enhance viral gene expression for multiple viral families, although the in vivo significance is unknown. The mechanistic basis for HSP-mediated increases in viral gene expression has been addressed only for DNA viruses and retroviruses, until our work with the paramyxoviruses measles (MV) and canine distemper virus (CDV). Data from our previous funding interval show that the major inducible 70 kDa HSP (hsp72) interacts with two discrete binding motifs (Box-2 and Box-3) on the C- terminus of the MV nucleocapsid protein (N), where Box-3 mediates stimulation of transcription by hsp72 but not the observed increases in genome replication. Aim one of the current proposal tests the hypothesis that hsp72 binding to Box-2 mediates stimulation of genome replication, and a structure-based approach will be used to understand mechanisms underlying the separable effects of hsp72 on transcription and genome replication. Aim two determines the in vivo significance of these MV-HSP interactions using a mouse model of brain infection. Elevation of hsp72 levels in neurons at the time of MV challenge results in either enhanced neurovirulence or clearance depending upon mouse strain. It is our hypothesis that hsp72-dependent susceptibility to infection reflects H-2 restricted differences in virus specific T cell responses mediating viral clearance, and the degree of viral hsp72-responsiveness mediated by Box-2 and Box-3. By this model, hsp72-dependent increases in viral antigen expression facilitate adaptive immune responses leading to clearance, although such a protective host response backfires if T cell responses are not adequate to contain the burst in viral replication, leading to increased neurovirulence. In either setting, virus of reduced hsp72 responsiveness would be more prone to establish stable persistent infection. Importantly, these viral and host determinants of neurovirulence have potential broad relevance to other neurotropic Mononegavirales with similar mechanisms of regulated gene expression (e.g., rabies and Borna virus). Relevance to Public Health: Fever induces proteins in the brain that can either protect brain from viral infection or make that viral infection worse. Our work will identify the viral and host determinants of these two possible outcomes so that we may effectively treat the virus infected patient. The experimental system uses measles virus, but the work has potential broad relevance to other viruses that infect brain.

描述（由申请人提供）：细胞热休克蛋白（HSP）增强多个病毒家族的病毒基因表达，尽管体内意义尚不清楚。在我们对副粘病毒麻疹 (MV) 和犬瘟热病毒 (CDV) 进行研究之前，仅针对 DNA 病毒和逆转录病毒解决了 HSP 介导的病毒基因表达增加的机制基础。我们之前资助期间的数据显示，主要诱导型 70 kDa HSP (hsp72) 与 MV 核衣壳蛋白 (N) C 末端的两个离散结合基序（Box-2 和 Box-3）相互作用，其中 Box-3介导 hsp72 的转录刺激，但不介导观察到的基因组复制增加。当前提案的目标之一测试了 hsp72 与 Box-2 结合介导基因组复制刺激的假设，并且将使用基于结构的方法来了解 hsp72 对转录和基因组复制的可分离影响的机制。目标二使用小鼠脑感染模型确定这些 MV-HSP 相互作用的体内意义。 MV 攻击时神经元中 hsp72 水平的升高会导致神经毒力增强或清除，具体取决于小鼠品系。我们的假设是，hsp72 依赖性感染易感性反映了介导病毒清除的病毒特异性 T 细胞反应的 H-2 限制性差异，以及 Box-2 和 Box-3 介导的病毒 hsp72 反应程度。通过该模型，hsp72依赖性病毒抗原表达的增加促进了适应性免疫反应，从而导致清除，尽管如果T细胞反应不足以遏制病毒复制的爆发，这种保护性宿主反应会适得其反，从而导致神经毒力增加。在任何一种情况下，hsp72 反应性降低的病毒都更容易建立稳定的持续感染。重要的是，这些神经毒力的病毒和宿主决定因素与具有类似基因表达调节机制的其他嗜神经性单股病毒（例如狂犬病和博尔纳病毒）具有潜在广泛的相关性。与公共卫生的相关性：发烧会在大脑中产生蛋白质，这些蛋白质可以保护大脑免受病毒感染，也可以使病毒感染恶化。我们的工作将确定这两种可能结果的病毒和宿主决定因素，以便我们可以有效地治疗病毒感染的患者。该实验系统使用麻疹病毒，但这项工作与感染大脑的其他病毒具有潜在广泛的相关性。