Mechanisms of Cell Signaling by the Human Cytomegalovirus US27 Gene Product

描述（由申请人提供）：人类巨细胞病毒（HCMV）是一种广泛存在的病原体，它设计了许多逃避宿主免疫系统的机制。其中一种策略涉及分子模仿，即表达功能与宿主蛋白质相似的蛋白质。US27基因产物是预测的g蛋白偶联受体，与人趋化因子受体具有同源性。本研究申请的具体目标是研究该受体对细胞生长和存活的影响，识别结合US27的配体，并表征下游信号事件，目的是了解这种病毒编码受体如何利用细胞信号传导来获取病毒的优势。我们假设在病毒感染期间，US27通过干扰正常的趋化因子信号通路来改变免疫细胞之间的通讯。这是基于观察到US27基因产物包含许多细胞趋化因子受体共同的特征，以及US27在HCMV感染细胞中表达并存在于感染性病毒粒子的包膜中的发现。虽然US27基因在体外裂解复制中不是必需的，但这可能表明在体内HCMV感染的其他方面起作用，如免疫调节、发病机制或传播。提出的研究将提供一个彻底的表征这种病毒GPCR。我们将a)检查US27诱导细胞周期阻滞或触发细胞凋亡的能力，b)使用受体嵌合体鉴定US27配体以筛选人类趋化因子库，c)阐明US27所使用的细胞信号通路。这些研究的结果将更好地了解US27的分子作用，从而导致未来的研究可能阐明该蛋白在病毒感染中的作用，并为新型抗病毒治疗提供潜在的靶点。公共卫生相关性：机会致病菌如人类巨细胞病毒（HCMV）可在免疫系统受损的个体中引起严重疾病，如移植受者、艾滋病患者或新生儿。HCMV感染70-90%的普通人群，引起肺炎、视网膜炎和先天性缺陷，也与心血管疾病的加速有关。通过研究这种病原体与其人类宿主之间的分子相互作用，可能会发现新的抗病毒药物靶点，从而有可能降低人类的死亡率和疾病。

DESCRIPTION (provided by applicant): Human cytomegalovirus (HCMV) is a widespread pathogen that has devised numerous mechanisms for evading the host immune system. One such strategy involves molecular mimicry, the expression of proteins that functionally resemble host proteins. The US27 gene product is a predicted G-protein coupled receptor with homology to human chemokine receptors. The specific goals of this research application are to investigate the impact of this receptor on cell growth and survival, identify ligands that bind US27, and characterize downstream signaling events with the aim of understanding how this virally encoded receptor exploits cell signaling for the advantage of the virus. We hypothesize that US27 functions to alter communication between immune cells during virus infection by interfering with normal chemokine signaling. This is based on the observations the US27 gene product contains many features common to cellular chemokine receptors and the finding that US27 is expressed in HCMV infected cells and present in the envelope of infectious virions. While the US27 gene is non-essential for lytic replication in vitro, this may indicate a role in other aspects of HCMV infection in vivo, such as immune modulation, pathogenesis, or dissemination. The proposed study will provide a thorough characterization of this viral GPCR. We will a) examine the ability of US27 to induce cell cycle arrest or trigger apoptosis, b) identify US27 ligands using receptor chimeras to screen a library of human chemokines, and c) elucidate cell signaling pathways employed by US27. The results of these studies will provide a better understanding of the molecular action of US27, leading to future studies that may clarify the role of this protein in virus infection and provide a potential target for novel anti-viral therapeutics. PUBLIC HEALTH RELEVANCE: Opportunistic pathogens like human cytomegalovirus (HCMV) can cause serious disease in individuals with compromised immune systems, such as transplant recipients, AIDS patients, or newborn infants. HCMV infects 70-90% of the general population, causing pneumonitis, retinitis, and congenital defects, and it has also been implicated in the acceleration of cardiovascular disease. By studying the molecular interactions between this pathogen and its human host, novel antiviral drug targets may be identified, potentially leading to decreased human mortality and disease.