Inflammatory Mediators of Gammaherpesvirus Reactivation

描述(申请人提供)：人类伽马疱疹病毒是爱泼斯坦-巴尔病毒(EBV)和卡波西肉瘤相关疱疹病毒(KSHV)，也称为人类疱疹病毒8(HHV-8)。每一种人类伽马疱疹病毒都与许多恶性肿瘤密切相关，特别是在免疫抑制的移植受者或因同时感染人类免疫缺陷病毒而免疫抑制的个人中。像其他疱疹病毒一样，伽马疱疹病毒的特点是能够在宿主细胞中建立潜伏期。从潜伏期和随后的裂解病毒复制中重新激活是伽马疱疹病毒生命周期的重要组成部分，使病毒能够传播到宿主内的其他细胞或其他易受感染的宿主。伽马疱疹病毒重新激活过程中潜在的分子机制越来越被理解，但触发这些分子事件的特定外源刺激尚未很好地确定。临床和实验证据表明，与第二种病原体混合感染可能会刺激潜伏感染伽马疱疹病毒的宿主重新激活。使用混合感染的小鼠模型，这项应用将检验以下假设：急性感染第二种病原体能够诱导潜伏的小鼠伽马疱疹病毒68(MHV-68)重新激活。其具体目的是1)确定混合感染是否诱导潜伏的MHV-68重新激活，以及2)确定特定的趋化因子和细胞因子在潜伏的MHV-68重新激活中的作用。与公共卫生相关：本申请中概述的实验将扩大我们对伽马疱疹病毒如何重新激活的理解，即在持续感染的人中从非活动状态唤醒，以便创建能够感染同一人体内其他细胞或感染其他人的病毒的新副本。从这些实验中获得的信息将大大有助于我们理解伽马疱疹病毒的生物学和发病机制，并可能对设计治疗伽马疱疹病毒相关疾病的策略产生影响。

DESCRIPTION (provided by applicant): The human gammaherpesviruses are Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). Each human gammaherpesvirus is closely associated with a number of malignancies, particularly in immunosuppressed transplant recipients or individuals with immunosuppression due to concurrent infection with human immunodeficiency virus. Like other herpesviruses, the gammaherpesviruses are characterized by their ability to establish latency in host cells. Reactivation from latency and subsequent lytic viral replication is an essential component of the gammaherpesvirus life cycle, allowing the virus to spread to other cells within the host or to other susceptible hosts. Molecular mechanisms underlying the process of gammaherpesvirus reactivation are increasingly understood, but specific exogenous stimuli that trigger these molecular events are not yet well defined. Clinical and experimental evidence suggests that coinfection with a second pathogen may serve as a stimulus for reactivation in a host latently infected with a gammaherpesvirus. Using a mouse model of coinfection, this application will test the hypothesis that acute infection with a second pathogen is capable of inducing reactivation of latent murine gammaherpesvirus 68 (MHV-68). The specific aims are to 1) determine whether coinfection induces reactivation of latent MHV-68, and 2) define the roles of select chemokines and cytokines in reactivation of latent MHV-68. Relevance to Public Health: The experiments outlined in this application will expand our understanding of how gammaherpesviruses reactivate, awakening from an inactive state in a persistently infected person in order to create new copies of virus capable of infecting other cells within the same person or infecting other individuals. Information gained from these experiments will contribute significantly to our understanding of gammaherpesvirus biology and pathogenesis and potentially will impact on strategies designed to treat gammaherpesvirus-related disease.