Analysis of HCMV Infection of Monocytes and Macrophages

项目总结： 人巨细胞病毒(HCMV)在免疫功能低下的宿主中引起严重疾病，在 有免疫能力的宿主。巨细胞病毒病涉及多个器官系统，因此是 感染是病毒的血源性传播。我们最近提供的证据表明单核细胞 巨噬细胞是病毒传播和终生持续的主要细胞类型。我们的数据 建议使用以下模式进行病毒传播。单核细胞在血液中被感染，尽管不是生产性的。 在最初感染时，并由病毒与同源受体结合诱导渗入 各种纸巾。在那里，它们分化成长寿的巨噬细胞，支持复制 原始病毒，允许病毒在目标器官中持续存在。驱使单核细胞外渗和 单核细胞向巨噬细胞分化似乎是巨细胞病毒的基本功能。我们的结果是 临床证据支持，表明利用单核细胞和巨噬细胞治疗 病毒的传播和持续将巨细胞病毒感染与病毒介导的致病机制联系起来。 巨细胞病毒如何影响单核细胞功能并迫使感染的单核细胞充当特洛伊木马 马匹用于血源性传播？我们的新数据表明，病毒结合是引发 感染过程中单核细胞的变化。病毒与单核细胞上的同源细胞受体结合使 作为基本分子决定因素的宿主信号通路的成功操纵 用于病毒传播。随着最近在成纤维细胞(表皮)上发现了巨细胞病毒受体 生长因子受体(EGFR)和细胞整合素)，以及我们的新数据表明，EGFR和 整合素是单核细胞上真正的受体，它将病毒结合与细胞内独特的功能变化联系起来。 单核细胞，我们现在准备破译巨细胞病毒操纵单核细胞功能的机制。 我们假设，一种独特的HCMV介导的受体/配体相互作用的组合 在受感染的单核细胞中触发明显和特定的变化，促进病毒的持久性。为了测试 我们的假设是，我们将检验巨细胞病毒糖蛋白与单核细胞和巨噬细胞的功能结合 触发生物学变化；研究单核细胞中巨细胞病毒信号介导的转录组 巨噬细胞；以及，确定病毒介导的信号促进的细胞机制 单核细胞的运动和存活。这项研究的结果将通过以下方式为机制提供新的见解 哪种HCMV感染会在感染的单核细胞中引发独特的分子变化并进入潜在的 巨细胞病毒的致病原因，以及寻找新的潜在的治疗干预靶点。

PROJECT SUMMARY: Human cytomegalovirus (HCMV) causes severe disease in immunocompromised hosts, as well as in immunocompetent hosts. HCMV disease involves multiple organ systems, thus an essential feature of infections is the hematogenous dissemination of the virus. We recently provided evidence that monocytes and macrophages are principal cell types responsible for viral spread and life-long persistence. Our data suggest the following model for viral spread. Monocytes are infected in the blood, although not productively at the time of initial infection, and are induced by viral binding to cognate receptors to extravasate into various tissues. There they differentiate into long-lived macrophages, which support replication of the original virus, allowing for viral persistence in target organs. The ability to drive monocyte extravasation and monocyte-to-macrophage differentiation appears to be an essential function of HCMV. Our results are supported by clinical evidence, suggesting that the strategy of utilizing monocytes and macrophages for viral dissemination and persistence links HCMV infection to viral-mediated pathogenesis. How does HCMV influence monocyte function and force the infected monocyte to serve as Trojan Horses for hematogenous spread? Our new data show that viral binding is the key biological trigger for the changes in monocytes during infection. Viral binding to cognate cellular receptors on monocytes allows for the successful manipulation of the host-signaling pathways that serve as essential molecular determinants for viral dissemination. With the recent identification of HCMV receptors on fibroblasts (the epidermal growth factor receptor (EGFR) and cellular integrins), along with our new data showing that EGFR and integrins are bona fide receptors on monocytes that link viral binding to the unique functional changes in monocytes, we are now poised to decipher mechanisms by which HCMV manipulates monocyte function. We hypothesize that a unique combination of HCMV-mediated receptor/ligand interactions triggers distinct and specific changes in infected monocytes that promote viral persistence. To test our hypothesis, we will examine if HCMV glycoprotein binding to monocytes and macrophages functionally triggers biological changes; investigate the HCMV-signal-mediated transcriptome in monocytes and macrophages; and, determine the cellular mechanisms by which viral-mediated signaling promotes monocyte motility and survival. The results from this study will provide new insight into the mechanisms by which HCMV infection initiates unique molecular changes in infected monocytes and into the underlying causes of HCMV pathogenesis, as well as identify new potential targets for therapeutic intervention.