Heat shock protein modulation of paramyxoviral disease

描述（由申请人提供）：细胞热休克蛋白（HSPs）在生理刺激（如发烧）后产生高水平。当释放到细胞外环境时，热休克蛋白刺激促炎细胞因子反应，激活抗原递呈细胞，介导抗原交叉递呈。热休克蛋白还刺激多个病毒家族的基因表达，引起病毒细胞病变效应增加。热休克蛋白对病毒毒力的这些看似截然相反的作用（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得到证实。我们的假设是，在免疫能力强的宿主中，热休克蛋白的诱导对宿主具有保护作用，热休克蛋白的直接免疫刺激作用和/或热休克蛋白介导的病毒抗原负担的增加促进了适应性抗病毒免疫反应，从而导致病毒清除。目前的探索性/发展性研究拨款提案将通过热休克蛋白的药理学诱导（即GGA治疗）来改变棉花大鼠呼吸道感染麻疹病毒（MV）的结果，测试对野生型和疫苗MV株免疫反应的影响。棉花大鼠对野生型和疫苗型MV气道攻击的病毒学和免疫学反应已经确定。MV对热休克蛋白的反应性也有很好的定义，因此，具有或缺乏对热休克蛋白转录反应的病毒之间感染结果的差异可以用来确定热休克蛋白依赖的病毒基因表达增加在多大程度上决定免疫后遗症。结果将作为未来研究的基础，包括确定GGA治疗的潜在免疫机制，并建立我们的发现与相关病毒系统的更广泛相关性（例如，人类呼吸道合胞病毒，其复制和宿主免疫反应也可以在棉花大鼠中建模）。

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.