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Characterization of Viral Receptors and Signaling Networks in JC Polyomavirus Infection

JC 多瘤病毒感染中病毒受体和信号网络的表征

基本信息

批准号：
10437461
负责人：
Melissa Maginnis
金额：
$ 44.04万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-04 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437461
关键词：
ADRBK1 gene Acquired Immunodeficiency Syndrome Antiviral Therapy Astrocytes Biochemical Biological Assay Brain Cells Chronic Clathrin Complex Confocal Microscopy Coronavirus Data Demyelinating Diseases Development Disease Ebola Hemorrhagic Fever Ebola virus Endocytosis Event G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors Goals HIV Health Herpesviridae Human Immune Immunocompromised Host Immunosuppression Individual Infection Invaded JC Virus Kidney Knowledge Left Ligand Binding Ligands Lytic Phase Marburgvirus Mediating Microscopy Mitogen-Activated Protein Kinases Multiple Sclerosis Mutagenesis Neuraxis Neuroglia Oligodendroglia Outcome Pathogenesis Pattern Pharmaceutical Preparations Polyomavirus Polyomavirus Infections Population Predisposition Prevalence Process Progressive Multifocal Leukoencephalopathy Proteins Publishing Receptor Cell Receptor Signaling Reporting Research Resolution Risk Role Scaffolding Protein Serotonin Signal Pathway Signal Transduction Small Interfering RNA Sorting - Cell Movement Symptoms Testing Therapeutic Viral Virus Virus Activation Virus Diseases Virus Receptors Virus Replication Work beta-arrestin design effective therapy human disease immunomodulatory therapies immunosuppressed improved inhibitor insight kidney infection live cell imaging prevent receptor recruit serotonin receptor trafficking

项目摘要

PROJECT SUMMARY The objective of the proposed research is to determine the mechanisms by which JC polyomavirus (JCPyV) interacts with host-cell receptors to cause JCPyV infection, which leads to the development of progressive multifocal leukoencephalopathy (PML). JCPyV infects the majority of the human population and establishes a lifelong, asymptomatic infection in the kidney of healthy individuals. In immunocompromised individuals, JCPyV can spread to the central nervous system (CNS) and cause a lytic infection in glial cells, resulting in the fatal, demyelinating disease PML. Approximately 5% of individuals with HIV develop PML, which proves to be a terminal AIDS-defining illness, and individuals receiving immunomodulatory therapies for diseases including multiple sclerosis are at heightened risk for PML development. PML can be fatal within one year of symptom onset, especially when underlying immunosuppression is left untreated, and there are currently no approved treatments for this devastating disease. The mechanisms by which JCPyV engages cellular receptors to invade host cells to cause infection is not well characterized. Virus-receptor interactions regulate host cell susceptibility and disease pathogenesis, thus understanding JCPyV interactions with host cell receptors will provide key insight into the mechanisms of JCPyV invasion and infection of host cells. Our previous work elucidated that JCPyV entry is mediated by the 5-hydroxytryptamine 2 subfamily of serotonin receptors (5- HT2Rs) via clathrin-mediated endocytosis and β-arrestin. We also determined that JCPyV infection induces clustering of 5-HT2Rs. Interestingly, G-protein coupled receptors (GPCR), including 5-HT2Rs, can cluster to form hetero- and homodimers as well as oligomers, which is functionally significant to the structural organization of the ligand binding interface, endocytic mechanisms, and activation of and signaling pathways. However, this process is not well characterized for 5-HT2Rs, and how receptor attributes direct viral invasion of host cells and orchestrate the complex processes of viral infection is poorly understood. We hypothesize that JCPyV infection induces ligand-specific cluster patterns of 5-HT2Rs to mediate JCPyV entry, trafficking, and receptor-activated signaling pathways. Three complementary specific aims are proposed in this research plan to understand the mechanisms by which JCPyV utilizes 5-HT2Rs to internalize into host cells and usurp cellular signaling networks to regulate viral trafficking and drive viral replication. This research will enhance our understanding of JCPyV entry and signaling, elucidating how virus-receptor interactions regulate viral infection and disease. These studies could also uncover new antiviral targets or provide rationale for experimental use of on-market 5-HT2R-specific drugs for PML. Outcomes of this work will also provide broader insights into the mechanisms of virus entry of nonenveloped viruses and activation of cellular signaling networks by viruses implicated to utilize GPCR signaling such as coronaviruses, herpesviruses, and Ebola virus, which cause serious human diseases.

项目摘要这项研究的目的是确定JC多瘤病毒（JCPyV）与宿主细胞受体相互作用，引起JCPyV感染，导致进行性多灶性白质脑病（PML）。JCPyV感染大多数人群，并建立了一个健康个体肾脏中的终身无症状感染。在免疫功能低下的个体中， JCPyV可以扩散到中枢神经系统（CNS）并在神经胶质细胞中引起溶解性感染，导致神经胶质细胞的损伤。致命的脱髓鞘疾病PML。大约5%的HIV感染者会发展为PML，这被证明是晚期艾滋病定义疾病，以及接受免疫调节治疗的疾病，包括多发性硬化症患者发生PML的风险更高。PML可在出现症状后一年内致命发病，特别是当潜在的免疫抑制未经治疗，目前没有批准的治疗这种毁灭性的疾病。JCPyV与细胞受体结合的机制，侵入宿主细胞引起感染特征还不清楚。病毒-受体相互作用调节宿主细胞因此，了解JCPyV与宿主细胞受体的相互作用，为深入了解JCPyV入侵和感染宿主细胞的机制提供了关键信息。我们以前的工作阐明了JCPyV进入是由5-羟色胺2亚家族的5-羟色胺受体（5-羟色胺2）介导的。 HT 2 Rs）通过网格蛋白介导的内吞作用和β-抑制蛋白。我们还确定了JCPyV感染诱导 5-HT 2 R的聚集。有趣的是，G蛋白偶联受体（GPCR），包括5-HT 2 R，可以聚集到形成异二聚体和同二聚体以及低聚体，这对结构的功能性重要。配体结合界面的组织、内吞机制以及信号通路的激活。然而，对于5-HT 2 R，该过程没有很好地表征，以及受体如何属性直接病毒入侵。宿主细胞和编排病毒感染的复杂过程的理解很少。我们假设 JCPyV感染诱导5-HT 2 R的配体特异性簇模式以介导JCPyV进入、运输和代谢。受体激活的信号通路。本研究提出了三个互补的具体目标计划了解JCPyV利用5-HT 2 R内化到宿主细胞中的机制，篡夺细胞信号网络来调节病毒运输和驱动病毒复制。本研究将增强我们对JCPyV进入和信号传导的理解，阐明病毒-受体相互作用如何调节病毒感染和疾病。这些研究还可以发现新的抗病毒靶点或提供理论依据用于实验性使用市售5-HT 2 R特异性药物治疗PML。这项工作的成果还将提供对病毒进入无包膜病毒和激活细胞信号传导的机制有更广泛的了解涉及利用GPCR信号传导的病毒网络，如冠状病毒、疱疹病毒和埃博拉病毒病毒，导致严重的人类疾病。