Mechanisms of HCMV-induced monocyte-to-macrophage differentiation.

HCMV 诱导单核细胞向巨噬细胞分化的机制。

• 批准号: 10057351
• 负责人: Gary Ching Tao Chan
• 金额: $ 53.53万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-11-09 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057351
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Antiviral Agents; Apoptotic; Atherosclerosis; Binding; Blood Circulation; Cell surface; Cells; Chronic; Complex; Complication; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease; Ensure; Etiology; Glycoproteins; Growth Factor; HSPB1 gene; Human; Immunocompetent; Immunocompromised Host; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intervention; Lead; MCL1 gene; Maps; Mediating; Morbidity - disease rate; Multiple Organ Failure; Myelogenous; Organ; Output; Pathogenesis; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Play; Principal Investigator; Prognosis; Protein Isoforms; Proteins; Receptor Signaling; Regimen; Resolution; Role; Serine; Signal Transduction; Site; Small Interfering RNA; Specificity; Substrate Specificity; Testing; Threonine; Tissues; Translations; Transplant Recipients; Up-Regulation; Viral; Viral Proteins; Virus; Virus Replication; chronic inflammatory disease; design; dissemination strategy; genetic approach; high risk; immunosuppressed; improved; ineffective therapies; inhibitor/antagonist; inositol-1,4,5-trisphosphate 5-phosphatase; macrophage; monocyte; mortality; neonate; neutralizing antibody; novel; novel therapeutics; peripheral blood; post-transplant; prevent; receptor; side effect; small molecule inhibitor; therapy design; tripolyphosphate

Human cytomegalovirus (HCMV) infection is generally asymptomatic in immunocompetent individuals, although HCMV is a primary viral candidate in the etiology of several chronic inflammatory diseases including atherosclerosis and inflammatory bowel disease. In immunocompromised individuals, such as neonates, AIDS patients, and transplant recipients, HCMV infection can lead to acute multi-organ inflammation resulting in significant morbidity and mortality. Inflammatory organ diseases associated with a HCMV infection is a direct consequence of the systemic viral spread to and infection of multiple organ sites that occur during either asymptomatic or symptomatic infections. Monocytes are responsible for delivering the virus into tissue and play a central role in the inflammatory state of infected organs. However, because anti-apoptotic viral proteins are not expressed during the early stages of infection, it remains unclear how HCMV promotes the survival and differentiation of these short-lived cells. We found that viral glycoproteins induced an atypical activation of Akt, a critical cell fate determinant of monocyte survival, during HCMV entry, which led to the upregulation of a specific subset of Akt-dependent pro-survival proteins required for the early anti-apoptotic state within infected monocytes. We found HCMV infection aberrantly regulated the phosphoinositide (principal investigator) signaling network, which is responsible for modulating Akt activity. Thus, we hypothesize that HCMV glycoproteins stimulate a unique activation of Akt leading to the expression of select cellular anti-apoptotic proteins specifically required for the survival of infected monocytes. Aim 1 will delineate the role of viral glycoproteins in modulating the principal investigator signaling necessary for the HCMV-specific activation of Akt. We will characterize the components of the glycoprotein-initiated principal investigator signaling receptor complex(es). Additionally, the functional role of each component within the HCMV-induced principal investigator signaling complex(es) will be confirmed using a combination of soluble glycoproteins, neutralizing antibodies, small-molecule inhibitors, and siRNAs. Aim 2 will determine the mechanism by which the HCMV-initiated principal investigator signaling network aberrantly regulates Akt activity. We will map the glycoprotein-driven cellular signaling network used to induce the atypical activation of Akt using siRNAs and small-molecule inhibitors. In conjunction, we will determine how coordinated signaling from glycoproteins alters the substrate specificity of Akt using glycoprotein-neutralized HCMV and soluble glycoproteins. Aim 3 will elucidate the unique HCMV-induced monocyte pro-survival translational landscape generated by the aberrant activation of Akt. We will examine the role of HCMV-activated Akt in stimulating the synthesis of select survival proteins by altering the HCMV-specific principal investigator signaling network. The function of newly identified virus-induced survival proteins will be confirmed by small-molecule inhibitors and genetic approaches. These studies will increase our understanding about the mechanisms of HCMV pathogenesis and dissemination.

人巨细胞病毒（HCMV）感染在免疫功能正常的个体中通常是无症状的，尽管HCMV是几种慢性炎性疾病（包括动脉粥样硬化和炎性肠病）的病因学中的主要病毒候选者。在免疫功能低下的个体中，如新生儿、AIDS患者和移植受者，HCMV感染可导致急性多器官炎症，从而导致显著的发病率和死亡率。与HCMV感染相关的炎性器官疾病是在无症状或有症状感染期间发生的全身性病毒扩散至多个器官部位并感染的直接后果。单核细胞负责将病毒输送到组织中，并在受感染器官的炎症状态中发挥核心作用。然而，由于抗凋亡病毒蛋白在感染的早期阶段不表达，因此仍然不清楚HCMV如何促进这些短寿命细胞的存活和分化。我们发现，病毒糖蛋白诱导Akt的非典型激活，单核细胞存活的关键细胞命运决定因素，在HCMV进入，这导致特定的Akt依赖性促生存蛋白的子集的上调所需的早期抗凋亡状态感染的单核细胞。我们发现HCMV感染异常调节磷酸肌醇（主要研究者）信号网络，这是负责调节Akt活性。因此，我们假设HCMV糖蛋白刺激Akt的独特激活，导致受感染单核细胞存活所需的选择性细胞抗凋亡蛋白的表达。目的1将描述病毒糖蛋白在调节HCMV特异性Akt激活所必需的主要研究者信号传导中的作用。我们将描述糖蛋白启动的主要研究者信号受体复合物的组成部分。此外，将使用可溶性糖蛋白、中和抗体、小分子抑制剂和siRNA的组合来确认HCMV诱导的主要研究者信号传导复合物中各组分的功能作用。目的2将确定HCMV启动的主要研究者信号网络异常调节Akt活性的机制。我们将绘制糖蛋白驱动的细胞信号网络，用于使用siRNA和小分子抑制剂诱导Akt的非典型激活。结合，我们将确定如何协调信号从糖蛋白改变Akt的底物特异性使用糖蛋白中和的HCMV和可溶性糖蛋白。目的3将阐明独特的HCMV诱导的单核细胞促生存翻译景观所产生的异常激活Akt。我们将研究HCMV激活的Akt通过改变HCMV特异性主要研究者信号网络在刺激选择的存活蛋白合成中的作用。新发现的病毒诱导的存活蛋白的功能将通过小分子抑制剂和遗传方法来证实。这些研究将有助于加深对HCMV致病和传播机制的认识。