Heat shock protein modulation of paramyxoviral disease

描述（由申请人提供）：细胞热休克蛋白（HSP）在生理刺激（如发热）后以高水平产生。当热休克蛋白释放到细胞外环境中时，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作用的结果（即，一方面促进免疫应答，另一方面促进病毒复制）尚未建立用于任何病毒系统。我们的假设是，HSP的诱导在免疫活性宿主内具有宿主保护性，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导致病毒清除的适应性抗病毒免疫应答。目前的探索性/发展性研究补助金提案将使用HSP的药理学诱导（即，GGA处理）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毒株的免疫应答的影响。棉鼠对野生型和疫苗MV的气道攻击的病毒学和免疫学应答是明确的。MV的HSP-反应性也被很好地定义，因此具有或缺乏对HSP的转录反应的病毒之间的感染结果的差异可用于确定病毒基因表达中HSP依赖性增加决定免疫后遗症的程度。结果将作为未来研究的基础，这些研究将包括鉴定GGA治疗效果的免疫学机制，并建立我们的发现与相关病毒系统（例如，人呼吸道合胞病毒，一种其复制和宿主免疫应答也可以在棉鼠中建模的因子）。 公共卫生相关性：发热是对许多病毒因子感染的一致反应，但尚不清楚发热诱导的蛋白质如HSP对宿主有益或有害的程度。我们的工作将确定HSP诱导药物（GGA）促进病原性MV分离株清除的能力，建立HSP诱导作为一种新的抗病毒策略的潜力。

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.