Heat shock protein modulation of paramyxoviral disease

副粘病毒病的热休克蛋白调节

基本信息

批准号：
7471216
负责人：
Michael J Oglesbee
金额：
$ 18.75万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7471216
关键词：
Acetone Address Amino Acids Antigen-Presenting Cells Antigens Antiviral Agents Antiviral Therapy Applications Grants Bacterial Infections Binding Binding Sites Brain Canine Distemper Categories Cell Death Cell Survival Cells Cellular Stress Response Child Complex Cotton Rats Cross Presentation DNA Viruses Development Disease Disease Progression Drug or chemical Tissue Distribution Emerging Communicable Diseases Environment Exhibits Family Family member Fever Foundations Future Gene Expression Genetic Transcription Genome Genomics Gossypium Hand Heat shock proteins Human respiratory syncytial virus Immune Immune System Diseases Immune response Immunity In Vitro Infection Interstitial Pneumonia Investigation Kinetics Knowledge Lead Lung Lymphoid Tissue Macaca mulatta Measles Measles virus Mediating Modeling Modification Molecular Chaperones Neurons Nipah Virus Nucleocapsid Proteins Nucleosome Core Particle Outcome Paramyxovirus Pathway interactions Patients Peptides Pharmaceutical Preparations Physiological Polymerase Primates Production Protein Family Proteins Public Health RNA Relative (related person)Research Project Grants Respiratory Syncytial Virus Infections Safety Secondary to Signal Transduction Solubility Stimulus Subunit Vaccines Support System System Testing Tissues Translating United States National Institutes of Health Vaccination Vaccines Viral Viral Antigens Viral Cytopathogenic Effect Viral N Protein Virulence Virus Virus Diseases Work animal tissue base cell mediated immune response cytokine extracellular in vivo molecular mass mouse model novel pathogen protective effect protein expression protein function response thermal stress vaccine efficacy viral DNA virus core

项目摘要

DESCRIPTION (provided by applicant): Cellular heat shock proteins (HSPs) are produced at high levels following physiological stimuli such as fever. When released into the extracellular environment, HSPs stimulate proinflammatory cytokine responses, activate antigen presenting cells, and mediate cross-presentation of antigen. HSPs also stimulate gene expression of multiple virus families, causing increased viral cytopathic effect. The outcome of these seemingly diametrically opposed effects of HSP on viral virulence (i.e., promoting immune responses on one hand, and promoting viral replication on the other) has not been established for any viral system. It is our hypothesis that induction of HSP is host protective within an immune competent host, where direct immunostimulatory effects of HSP and/or HSP-mediated increases in viral antigenic burden facilitate adaptive antiviral immune responses that lead to viral clearance. The current Exploratory/Developmental Research Grant proposal will test this hypothesis using pharmacological induction of HSP (i.e., GGA treatment) to modify the outcome of measles virus (MV) airway infection in the cotton rat, testing the impact upon immune responses to wild type and vaccine MV strains. The virological and immunological responses of the cotton rat to airway challenge by wild type and vaccine MV are well-established. The HSP-responsiveness of MV is also well defined, so that differences in infection outcome between viruses that possess or lack a transcriptional response to HSP can be used to determine the degree to which HSP-dependent increases in viral gene expression determine immune sequela. Results will serve as the foundation for future studies that will include identification of immunological mechanisms underlying effects of GGA treatment and establishing the more broad relevance of our findings to related viral systems (e.g., human respiratory syncytial virus, an agent whose replication and host immune response can also be modeled in the cotton rat). PUBLIC HEALTH RELEVANCE: Fever is a consistent response to infection by numerous viral agents, yet it is unclear to what degree fever-induced proteins such as HSP are beneficial or detrimental to the host. Our work will identify the ability of an HSP-inducing drug (GGA) to promote clearance of a pathogenic MV isolate, establishing the potential of HSP induction to serve as a novel antiviral strategy.

描述（由申请人提供）：细胞热休克蛋白（HSP）在生理刺激（例如发烧）后产生高水平。当释放到细胞外环境中时，HSP 会刺激促炎细胞因子反应，激活抗原呈递细胞，并介导抗原的交叉呈递。热休克蛋白还刺激多个病毒家族的基因表达，导致病毒细胞病变效应增加。 HSP 对病毒毒力的这些看似截然相反的影响（即一方面促进免疫反应，另一方面促进病毒复制）的结果尚未在任何病毒系统中确定。我们的假设是，HSP 的诱导在免疫能力强的宿主内具有宿主保护作用，其中 HSP 的直接免疫刺激作用和/或 HSP 介导的病毒抗原负荷增加促进适应性抗病毒免疫反应，从而导致病毒清除。目前的探索性/发展研究拨款提案将使用 HSP 的药理学诱导（即 GGA 治疗）来测试这一假设，以改变棉鼠中麻疹病毒（MV）气道感染的结果，测试对野生型和疫苗 MV 株。棉鼠对野生型和疫苗 MV 的气道攻击的病毒学和免疫学反应已明确。 MV 的 HSP 反应性也被明确定义，因此具有或缺乏 HSP 转录反应的病毒之间感染结果的差异可用于确定 HSP 依赖性病毒基因表达增加决定免疫后遗症的程度。结果将作为未来研究的基础，包括识别 GGA 治疗潜在影响的免疫机制，并建立我们的研究结果与相关病毒系统（例如，人类呼吸道合胞病毒，一种其复制和宿主免疫反应）的更广泛相关性。也可以在棉鼠中建模）。公共卫生相关性：发烧是对多种病毒感染的一致反应，但目前尚不清楚发烧诱导的蛋白质（如热休克蛋白）在多大程度上对宿主有益或有害。我们的工作将确定 HSP 诱导药物 (GGA) 促进致病性 MV 分离株清除的能力，确定 HSP 诱导作为新型抗病毒策略的潜力。