Analysis of HCMV Infection of Monocytes and Macrophages

描述(申请人提供)：人类巨细胞病毒(HCMV)会在免疫功能低下的宿主和免疫能力强的宿主中引起严重疾病。巨细胞病毒病涉及多个器官系统，因此感染的一个基本特征是病毒的血源性传播。我们最近提供的证据表明，单核细胞和巨噬细胞是导致病毒传播和终生持续的主要细胞类型。我们的数据为病毒传播提供了以下模型。单核细胞在血液中被感染，尽管在最初感染时不能产生生产力，并被病毒与同源受体结合诱导外渗到各种组织中。在那里，它们分化成长寿的巨噬细胞，支持原始病毒的复制，允许病毒在目标器官中持续存在。促进单核细胞外渗和单核细胞向巨噬细胞分化的能力似乎是巨细胞病毒的一项基本功能。我们的结果得到了临床证据的支持，表明利用单核细胞和巨噬细胞进行病毒传播和持续的策略将HCMV感染与病毒介导的致病联系起来。人巨细胞病毒如何影响单核细胞功能，迫使感染的单核细胞充当血源性传播的特洛伊木马？我们的新数据表明，病毒结合是感染过程中单核细胞变化的关键生物学触发因素。病毒与单核细胞上的同源细胞受体结合，可以成功地操纵宿主信号通路，而宿主信号通路是病毒传播的关键分子决定因素。随着最近对成纤维细胞上的HCMV受体(表皮生长因子受体(EGFR)和细胞整合素)的鉴定，以及我们的新数据显示EGFR和整合素是单核细胞上真正的受体，将病毒结合与单核细胞独特的功能变化联系起来，我们现在准备破译HCMV操纵单核细胞功能的机制。我们假设，HCMV介导的受体/配体相互作用的独特组合会在受感染的单核细胞中触发独特和特异的变化，从而促进病毒的持久性。为了验证我们的假设，我们将检查HCMV糖蛋白与单核细胞和巨噬细胞结合是否在功能上触发生物学变化；研究单核细胞和巨噬细胞中HCMV信号介导的转录组；并确定病毒介导的信号促进单核细胞运动和存活的细胞机制。这项研究的结果将为深入了解HCMV感染在感染单核细胞中启动独特的分子变化的机制以及HCMV发病的潜在原因提供新的见解，并为治疗干预寻找新的潜在靶点。公共卫生相关性：人类巨细胞病毒导致先天性感染的婴儿、移植和艾滋病患者的严重疾病，并被认为是心血管疾病发展和严重程度的强烈风险因素。通过定义病毒在宿主内传播的机制以及病毒如何建立终生持久性，我们提供了对潜在病毒发病机制的基本见解，并为治疗或药物干预开辟了新的潜在靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Human cytomegalovirus causes severe disease in congenitally infected infants, in transplant and AIDS patients, and is considered a strong risk factor for the development and severity of cardiovascular diseases. By defining the mechanisms of viral spread within the host and how the virus establishes life-long persistence, we provide fundamental insight into the underlying viral pathogenesis, as well as open up new potential targets for therapeutic or pharmacological intervention.