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：
7465390
负责人：
Michael J Oglesbee
金额：
$ 22.48万
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 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7465390
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）：尽管体内意义尚不清楚，但细胞热休克蛋白（HSP）增强了多个病毒家族的病毒基因表达。 HSP介导的病毒基因表达增加的机械基础仅针对DNA病毒和逆转录病毒，直到我们使用帕托氏菌病毒麻疹（MV）和犬distemper病毒（CDV）。我们以前的资金间隔的数据表明，在MV Nucleocapsid蛋白（N）的C末端上，主要诱导的70 kDa HSP（HSP72）与两个离散的结合基序（Box-2和Box-3）相互作用，其中Box-3介导HSP72的转录刺激，但观察到的基因组中的刺激却没有增加。目的是当前的提案测试之一，即HSP72与Box-2结合的假设介导了基因组复制的刺激，并且基于结构的方法将用于理解HSP72对转录和基因组复制的可分离作用的基础机制。目标两个决定使用脑感染的小鼠模型这些MV-HSP相互作用的体内意义。 MV挑战时神经元中HSP72水平的升高会导致神经动力率增强或取决于小鼠菌株。我们的假设是，HSP72依赖性感染的敏感性反映了H-2限制病毒特异性T细胞反应的差异，介导病毒清除率，以及Box-2和Box-2和Box-3介导的病毒HSP72响应程度。通过该模型，病毒抗原表达的Hsp72依赖性增加促进了适应性免疫反应，尽管如果T细胞反应不足以包含病毒复制中的爆发，导致神经毒害增加的情况下，则这种保护性宿主反应适得其反。在这两种情况下，HSP72响应性降低的病毒将更容易建立稳定的持续感染。重要的是，这些病毒性和宿主的神经电动电机的决定因素具有与其他神经性单核病毒具有相似机制具有相似基因表达（例如狂犬病和伯尔塔病毒）的机制的潜在广泛相关性。与公共卫生有关：发烧诱导大脑中的蛋白质，可以保护大脑免受病毒感染或使病毒感染恶化。我们的工作将确定这两个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感染病毒的患者。实验系统使用麻疹病毒，但该工作与感染大脑的其他病毒具有潜在的广泛相关性。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The measles virus N(TAIL)-XD complex: an illustrative example of fuzziness.

DOI：
10.1007/978-1-4614-0659-4_8
发表时间：
2012
期刊：
Advances in experimental medicine and biology
影响因子：
0
作者：
S. Longhi
通讯作者：
S. Longhi

The intrinsically disordered C-terminal domain of the measles virus nucleoprotein interacts with the C-terminal domain of the phosphoprotein via two distinct sites and remains predominantly unfolded.

DOI：
10.1110/ps.051411805
发表时间：
2005-08
期刊：
PROTEIN SCIENCE
影响因子：
8
作者：
Bourhis, Jean-Marie;Receveur-Brechot, Veronique;Oglesbee, Michael;Zhang, Xinsheng;Buccellato, Matthew;Darbon, Herve;Canard, Bruno;Finet, Stephanie;Longhi, Sonia
通讯作者：
Longhi, Sonia

Hyperthermic pre-conditioning promotes measles virus clearance from brain in a mouse model of persistent infection.

在持续感染的小鼠模型中，高温预处理可促进麻疹病毒从大脑中清除。

DOI：
10.1016/j.brainres.2003.12.041
发表时间：
2004
期刊：
Brain research.
影响因子：
0
作者：
Carsillo,Thomas;Carsillo,Mary;Niewiesk,Stefan;Vasconcelos,Daphne;Oglesbee,Michael
通讯作者：
Oglesbee,Michael

Intrinsic thermal resistance of the canine brain.

犬脑的固有热阻。

DOI：
10.1016/s0306-4522(02)00159-8
发表时间：
2002
期刊：
Neuroscience
影响因子：
3.3
作者：
Oglesbee,MJ;Alldinger,S;Vasconcelos,D;Diehl,KA;Shinko,PD;Baumgärtner,W;Tallman,R;Podell,M
通讯作者：
Podell,M

Extracellular hsp70 release in canine Steroid Responsive Meningitis-Arteritis.