Cellular Programming in Persistent Versus Lytic Viral Infections

持续性病毒感染与裂解性病毒感染中的细胞编程

基本信息

批准号：
10557026
负责人：
Melissa Maginnis
金额：
$ 26.24万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-05 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557026
关键词：
Acquired Immunodeficiency Syndrome Animal Model Astrocytes Biological Assay Biological Models Biology Brain Cell Communication Cell Culture Techniques Cell model Cells Central Nervous System Chronic Clathrin Comparative Genomic Analysis Coronavirus Cues Data Demyelinating Diseases Development Disease Disease Outcome Endocytosis G Protein-Coupled Receptor Signaling Gene Expression Genetic Transcription Goals Growth HIV Human Immune Immunocompromised Host Immunosuppression Individual Infection Invaded JC Virus Kidney Knowledge Left Lytic Lytic Phase Malignant Neoplasms Marketing Mediating Mitogen-Activated Protein Kinases Modeling Multiple Sclerosis Neuroglia Oligodendroglia Outcome Pathogenesis Pathology Pathway interactions Pharmaceutical Preparations Polyomavirus Infections Population Predisposition Prevalence Primary Cell Cultures Production Progressive Disease Progressive Multifocal Leukoencephalopathy Publishing Regulation Research Research Project Grants Risk Role Serotonin Signal Induction Signal Pathway Signal Transduction Testing Therapeutic Tissues Viral Viral Pathogenesis Virus Virus Diseases Virus Receptors Virus Replication Work antiviral drug development brain cell cell behavior cell growth regulation cell immortalization cell transformation cell type chronic infection combinatorial design effective therapy experimental study extracellular gain of function high throughput analysis high-throughput drug screening immunomodulatory therapies improved in vitro Model in vivo innovation insight kidney cell kidney infection loss of function novel pathogenic virus prevent programs protein expression receptor response serotonin receptor transcriptome sequencing transcriptomic profiling

项目摘要

CELLULAR REPROGRAMMING IN PERSISTENT VS. LYTIC VIRAL INFECTIONS PROJECT SUMMARY The long-range goal of the proposed research is to define the cellular factors that mediate JC polyomavirus (JCPyV) infection to better understand how virus-host cell interactions influence viral pathogenesis. JCPyV infects up to 80% of the population and establishes a lifelong, asymptomatic persistent infection in the kidneys of healthy individuals. However, 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 progressive multifocal leukoencephalopathy (PML). Approximately 5% of individuals with HIV develop PML, a terminal AIDS- defining illness, and individuals receiving immunomodulatory therapies for diseases including multiple sclerosis are at heightened risk for PML development. The increasing number of individuals receiving immunomodulatory therapies due to immune-mediated diseases has led to a rising number of PML cases in the past decade. Over 700 total cases of PML are due to a single drug class. PML can be fatal, especially when underlying immunosuppression is left untreated, and there are currently no approved treatments for this devastating disease. The lack of an animal model and limited cell culture models have largely restricted studies of JCPyV to a single transformed cell culture model. Recently-published studies have revealed that primary cell culture models are a better representation of disease pathogenesis in vivo, and thus we have developed innovative primary cell culture models to define cellular factors that are required for JCPyV infection. Two integrated specific aims are proposed in this research project to: 1) characterize cellular factors that mediate JCPyV entry and infection in primary cell types, and 2) elucidate cell-type dependent differences in persistent and lytic JCPyV infections. This research will enhance our understanding of how virus-host cell interactions influence disease outcomes and will serve as a platform for the development of antiviral treatments. Through this work, cellular factors required for JCPyV entry in primary cell types will be characterized through loss- and gain-of-function approaches using cell-based assays. Transcriptome profiling through RNA sequencing analysis will be used to determine how JCPyV infection alters gene expression in a cell-type dependent manner to identify pathways relevant to JCPyV pathogenesis and fatal disease outcomes. This combinatorial approach utilizes newly developed primary cell models of JCPyV infection and takes advantage of innovative high-throughput analysis of viral and cellular protein expression and RNA sequencing approaches. This research will fill key gaps in our knowledge of JCPyV biology and could elucidate novel antiviral targets or provide rationale for experimental use of on-market therapies to prevent or treat the fatal disease PML. Findings obtained from this research will also provide broader insights into the entry and signaling networks for other pathogenic viruses, like coronaviruses, and improve our understanding of dysregulation of cellular signaling in other diseases such as cancer.

在持久性VS中进行蜂窝重编程。裂解病毒感染项目摘要拟议的研究的远程目标是定义介导JC多瘤病毒的细胞因子（JCPYV）感染，以更好地了解病毒宿主细胞相互作用如何影响病毒发病机理。 jcpyv 感染多达80％的人口，并在肾脏中建立终生无症状的持续感染健康的个体。但是，在免疫功能低下的个体中，jcpyv可以传播到中枢神经系统（CNS）并引起神经胶质细胞的裂解感染，导致致命的脱髓鞘性疾病进行性多灶性白细胞病（PML）。大约5％的艾滋病毒患者发展为PML，这是一种末端艾滋病定义疾病，以及接受包括多发性硬化症在内的疾病的免疫调节疗法 PML开发的风险更高。接受免疫调节的个体数量增加在过去的十年中，由于免疫介导的疾病引起的疗法导致PML病例数量增加。超过 700例PML病例是由于单个药物类别引起的。 PML可能是致命的，尤其是在基础上免疫抑制未经治疗，目前没有批准的治疗方法疾病。缺乏动物模型和有限的细胞培养模型在很大程度上限制了JCPYV的研究单个转化的细胞培养模型。最近发表的研究表明，原代细胞培养模型是体内疾病发病机理的更好代表，因此我们发展了创新定义JCPYV感染所需的细胞因子的原代细胞培养模型。两个集成的特定该研究项目提出了目标：1）表征介导JCPYV进入和的细胞因素主要细胞类型的感染，以及2）阐明持久性和裂解JCPYV的细胞类型依赖性差异感染。这项研究将增强我们对病毒宿主相互作用如何影响疾病的理解结果，将作为开发抗病毒治疗的平台。通过这项工作，蜂窝 JCPYV进入主要细胞类型所需的因素将通过功能损失和功能来表征使用基于细胞的测定方法的方法。通过RNA测序分析进行转录组分析将用于确定JCPYV感染如何以细胞类型的方式改变基因表达以识别途径与JCPYV发病机理和致命疾病结局有关。这种组合方法使用了新的开发了JCPYV感染的主要细胞模型，并利用创新的高通量分析病毒和细胞蛋白表达和RNA测序方法这项研究将填补我们的关键空白了解JCPYV生物学并可以阐明新型的抗病毒靶标或为实验使用提供理由市场疗法可预防或治疗致命疾病PML。从这项研究获得的发现也将为其他病毒病毒（如冠状病毒，并提高我们对其他疾病（例如癌症）细胞信号传导失调的理解。