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。

基本信息

批准号：
10509383
负责人：
Gary Ching Tao Chan
金额：
$ 50.94万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-11-09 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509383
关键词：
Acquired Immunodeficiency Syndrome Acute Antiviral Agents Apoptotic Atherosclerosis Binding Cell surface Cells Chronic Circulation 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 MCL1 gene Macrophage 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 Induction 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 inorganic phosphate inositol-1,4,5-trisphosphate 5-phosphatase monocyte mortality neonate neutralizing antibody novel novel therapeutics peripheral blood permissiveness post-transplant prevent receptor side effect small molecule inhibitor therapy design tripolyphosphate

项目摘要

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.

尽管 HCMV 是多种慢性炎症性疾病（包括动脉粥样硬化和炎症性肠病）病因学中的主要候选病毒，但人类巨细胞病毒 (HCMV) 感染在免疫功能正常的个体中通常无症状。在免疫功能低下的个体中，例如新生儿、艾滋病患者和移植受者，HCMV 感染可导致急性多器官炎症，导致显着的发病率和死亡率。与 HCMV 感染相关的炎症器官疾病是无症状或有症状感染期间发生的全身性病毒扩散到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早期并不表达，因此目前尚不清楚HCMV如何促进这些短命细胞的存活和分化。我们发现，在 HCMV 进入期间，病毒糖蛋白诱导 Akt（单核细胞存活的关键细胞命运决定因素）非典型激活，从而导致早期抗凋亡状态所需的 Akt 依赖性促生存蛋白的特定子集上调在受感染的单核细胞内。我们发现 HCMV 感染异常调节磷酸肌醇（主要研究者）信号网络，该网络负责调节 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特定细胞抗凋亡蛋白的表达。目标 1 将描述病毒糖蛋白在调节 HCMV 特异性激活 Akt 所必需的主要研究者信号传导中的作用。我们将表征糖蛋白引发的主要研究者信号传导受体复合物的成分。此外，HCMV 诱导的主要研究者信号复合物中每个成分的功能作用将通过可溶性糖蛋白、中和抗体、小分子抑制剂和 siRNA 的组合来确认。目标 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。同时，我们将使用糖蛋白中和的 HCMV 和可溶性糖蛋白来确定糖蛋白的协调信号传导如何改变 Akt 的底物特异性。目标 3 将阐明由 Akt 异常激活产生的独特 HCMV 诱导的单核细胞促生存翻译景观。我们将通过改变 HCMV 特异性主要研究者信号网络来研究 HCMV 激活的 Akt 在刺激选择性生存蛋白合成中的作用。新发现的病毒诱导的生存蛋白的功能将通过小分子抑制剂和遗传方法得到证实。这些研究将增加我们对 HCMV 发病机制和传播机制的了解。