How does Cytomegalovirus use interferon lambda for optimal spread

项目摘要 虽然基本上没有症状，但人类巨细胞病毒(HCMV)可导致严重甚至致命的疾病 易感个体的子集。巨细胞病毒庞大的基因组使其能够致力于它的许多基因产品 优化宿主细胞的复制条件，对抗细胞应激和抗病毒反应。在……里面 在某些情况下，人巨细胞病毒甚至利用这些反应来促进感染。宿主干扰素系统，包括 I型(T1，a，b，e，k，w)，II(T2，g)和III(T3，L 1-4)干扰素已进化为介导先天抗病毒 豁免权。然而，我们发现用III型干扰素治疗，它对一些人有抗病毒的效果 包括流感和西尼罗河病毒在内的病毒，实际上增强了HCMV在这两种成纤维细胞中的传播 和上皮细胞。这些体外结果通过巨细胞病毒的动物模型得到了证实。更低的位置 与缺乏干扰素-L受体的小鼠相比，在几个器官中检测到巨细胞病毒感染水平 对野生型小鼠，证实了干扰素-L在促进巨细胞病毒感染和传播中的作用。这个 本方案中的实验将确定干扰素-L依赖的增强巨细胞病毒的机制 使用体外和体内系统进行感染。这将在两个具体目标下完成。第一个目标将定义 前病毒干扰素-L信号通路及其与提供抗病毒药物的通路的差异 环境。第二个目标将描述干扰素-L在体内感染过程中的性质，包括确定 干扰素-L产生的细胞来源及其介导的细胞和分子靶点的确定 前置效应。总体而言，这些研究将确定巨细胞病毒利用 正常情况下，抗病毒信号反应会增强传播。这些结果将为下一步的 研究对这一临床相关过程进行治疗干预的可能性。

Project Summary Although largely asymptomatic, human cytomegalovirus (HCMV) can cause severe and even fatal disease in a subset of susceptible individuals. The large genome of HCMV allows it to devote a number of its gene products to optimizing conditions for replication in the host cell and combat cellular stress and antiviral responses. In some cases, HCMV even exploits these responses to promote infection. The host interferon system, consisting of Type I (T1, a, b, e, k, w), II (T2, g) and III (T3, l 1-4) interferons, has evolved to mediate innate antiviral immunity. However, we found that treatment with Type III interferons, which antiviral effects against a number of viruses including influenza and West Nile viruses, actually enhances the spread of HCMV in both fibroblasts and epithelial cells. These in vitro results were confirmed using an animal model for cytomegalovirus. Lower levels of MCMV infection were detected in several organs of mice lacking the IFN-l receptor when compared to wildtype mouse, confirming a role for IFN-l in promoting cytomegalovirus infection and spread. The experiments in this proposal will define the mechanism for IFN-l-dependent enhancement of cytomegalovirus infection using both in vitro and in vivo systems. This will be done in two specific aims. The first aim will define the pathways involved in proviral IFN-l signaling and how they differ from those that confer an antiviral environment. The second aim will delineate the properties of IFN-l during in vivo infection, including defining the cellular source of IFN-l production and identifying the cellular and molecular IFN-l-targets that mediate the proviral effect. Overall, these studies will define the mechanism by which cytomegaloviruses utilize a normally antiviral signaling response to enhance spread. These results will provide the basis for additional studies investigating the potential for therapeutic intervention of this clinically relevant process.