Mechanisms of Cell Signaling by the Human Cytomegalovirus US27 Gene Product

人类巨细胞病毒 US27 基因产物的细胞信号传导机制

基本信息

批准号：
7456241
负责人：
JULIET VESCIO SPENCER
金额：
$ 21.23万
依托单位：
UNIVERSITY OF SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7456241
关键词：
Acceleration Acquired Immunodeficiency Syndrome Address Affect Affinity Antiviral Agents Apoptosis Binding Biological Biological Process CXCR3 gene Calcium Cardiovascular Diseases Cell Cycle Arrest Cell Cycle Progression Cell Line Cell Surface Receptors Cell Survival Cell physiology Cells Characteristics Chimera organism Chimeric Proteins Communication Congenital Abnormality Cyclic AMP Cytomegalovirus Cytomegalovirus Infections Disease Dose Drug Delivery Systems Event Family Future G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins General Population Genes Genome Goals Growth Hela Cells Heterotrimeric GTP-Binding Proteins Human Immune Immune response Immune system In Vitro Individual Induction of Apoptosis Infection Libraries Life Ligand Binding Ligand Binding Domain Ligands Membrane Molecular Molecular Mimicry Newborn Infant Normal Cell Orphan Outcome Pathogenesis Patients Personal Satisfaction Phase Physiological Pneumonia Production Proteins Public Health Rate Receptor Signaling Research Research Proposals Retinitis Role Second Messenger Systems Signal Pathway Signal Transduction Therapeutic Transplant Recipients Viral Viral Pathogenesis Virion Virus Virus Diseases base cell growth cell type chemokine chemokine receptor desensitization design extracellular follow-up human cytomegalovirus US27 protein human mortality immunoregulation in vivo latent infection lytic replication neonate novel pathogen protein activation protein expression receptor release of sequestered calcium ion into cytoplasm research study response second messenger stable cell line

项目摘要

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.

描述（由申请人提供）：人类巨细胞病毒（HCMV）是一种广泛传播的病原体，它设计了多种逃避宿主免疫系统的机制。其中一种策略涉及分子模拟，即功能上类似于宿主蛋白的蛋白质的表达。 US27基因产物是预测的G蛋白偶联受体，与人类趋化因子受体同源。这项研究应用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，并表征下游信号传导事件，目的是了解这种病毒编码的受体如何利用细胞信号传导来发挥其优势。病毒。我们假设 US27 通过干扰正常趋化因子信号传导来改变病毒感染期间免疫细胞之间的通讯。这是基于对 US27 基因产物包含许多细胞趋化因子受体共有的特征的观察，以及发现 US27 在 HCMV 感染的细胞中表达并存在于感染性病毒粒子的包膜中。虽然 US27 基因对于体外裂解性复制不是必需的，但这可能表明在体内 HCMV 感染的其他方面（例如免疫调节、发病机制或传播）中发挥作用。拟议的研究将提供该病毒 GPCR 的全面表征。我们将a）检查US27诱导细胞周期停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，以及c）阐明US27使用的细胞信号传导途径。这些研究的结果将有助于更好地理解 US27 的分子作用，从而促进未来的研究可能阐明这种蛋白质在病毒感染中的作用，并为新型抗病毒疗法提供潜在靶点。公共卫生相关性：人类巨细胞病毒 (HCMV) 等机会性病原体可能会导致免疫系统受损的个体（例如移植受者、艾滋病患者或新生儿）患上严重疾病。 HCMV 感染 70-90% 的普通人群，引起肺炎、视网膜炎和先天性缺陷，还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，可以确定新的抗病毒药物靶点，从而有可能降低人类死亡率和疾病。