Not just acute: IRF-7 has two site-specific functions against chronic gammaherpesvirus infection

建议书摘要 伽马疱疹病毒是一种普遍存在的病原体，可造成终生感染，由不同的 裂解和潜伏的生命周期。重要的是，人类伽马疱疹病毒在这两种疾病中都促进了多种癌症的发生。 具有免疫能力和免疫功能受损的宿主。虽然这些病毒驱动的癌症的风险因素很差 了解到，很明显，强劲的病毒驱动生发中心扩张，以及病毒的重新激活 潜伏期早于病毒致癌。因此，限制这两个过程的主机因素在 感染可能是潜在的治疗靶点。 由于人类伽马疱疹病毒的高流行率和巨大的物种特异性，小鼠 病原体小鼠疱疹病毒68(MHV68)被广泛用作伽马疱疹病毒的小动物模型 发病机制。该模型的一个特别优点是能够从基因上修改宿主以检查 控制感染的细胞和分子机制。对于这一型号，我们最近确定了 先前被低估的宿主因子IRF-7在伽马疱疹病毒中的新的和令人兴奋的功能 感染。具体地说，我们发现IRF-7在16岁时限制了伽马疱疹病毒驱动的生发中心的扩张 感染后几天。此外，我们发现在没有IRF-7的情况下，MHV68重新激活到更大的 来自腹膜细胞的频率与WT相比。这种表型在脾中未观察到。我们 假设IRF-7在宿主内的两个不同位置介导独立的抗病毒功能。 这里提出的体内实验将提供广泛的，但重点分析细胞和 免疫球蛋白IRF-7在宿主脾和腹膜中表达的分子意义 伽马疱疹病毒感染。重要的是，这些研究的成功完成将有助于深入了解 控制伽马疱疹病毒感染，这将为受感染的个人提供潜在的治疗目标 特别容易受到伽马疱疹病毒相关致癌效应的影响。

Proposal Summary Gammaherpesviruses are ubiquitous pathogens that establish lifelong infections and are defined by distinct lytic and latent lifecycles. Importantly, human gammaherpesviruses promote a variety of cancers in both immunocompetent and immunocompromised hosts. While risk factors for these virus-driven cancers are poorly understood, it is clear that robust virus-driven germinal center expansion, as well as reactivation of the virus from latency precedes viral oncogenesis. Therefore, host factors that restrict these two processes during infection may represent potential therapeutic targets. Due to the high prevalence and tremendous species specificity of human gammaherpesviruses, the mouse pathogen murine herpesvirus 68 (MHV68) is widely utilized as the small animal model of gammaherpesvirus pathogenesis. A particular strength of this model is the ability to genetically modify the host to examine the cellular and molecular mechanism by which infection is controlled. With this model we have recently identified new and exciting function of the previously underappreciated host factor IRF-7 during gammaherpesvirus infection. Specifically, we found that IRF-7 restricts gammaherpesvirus-driven germinal center expansion at 16 days post infection. Additionally, we found that in the absence of IRF-7, MHV68 reactivates to a greater frequency from peritoneal cells compared to WT. This phenotype was not observed in the spleen. We hypothesize that IRF-7 mediates independent antiviral functions in two separate sites within the host. The in vivo experiments proposed here will provide an extensive, yet focused analysis of the cellular and molecular importance of IRF-7 expression in both the spleen and peritoneal cavity of the host during gammaherpesvirus infection. Importantly, successful completion of these studies will provide insight into the control of gammaherpesvirus infections, which would offer potential therapeutic targets for infected individuals particularly susceptible to the associated oncogenic effects of gammaherpesviruses.