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

• 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
• 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

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.

持久VS中的细胞重编程溶血性病毒感染 项目总结 这项拟议研究的长期目标是确定介导JC多瘤病毒的细胞因素。 (JCPyV)感染，以更好地了解病毒与宿主细胞的相互作用如何影响病毒的致病。JCPyV 感染高达80%的人口，并在肾脏建立终身的、无症状的持续性感染 健康的个体。然而，在免疫受损的人中，JCPyV可以传播到中枢神经 系统(CNS)，并引起胶质细胞的裂解性感染，导致致命的进行性脱髓鞘疾病 多灶性白质脑病(PML)。大约5%的艾滋病毒携带者会患上PML，一种晚期艾滋病-- 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治疗的个人 患PML的风险很高。接受免疫调节剂治疗的人数不断增加 免疫介导性疾病的治疗在过去十年中导致了越来越多的PML病例。完毕 700例PML病例是由单一药物类别引起的。PML可能是致命的，特别是当 免疫抑制没有得到治疗，目前还没有批准的治疗方法来治疗这种毁灭性的疾病 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对JCPyV的研究 一个单一的转化细胞培养模型。最近发表的研究表明，原代细胞培养 模型更好地代表了体内的疾病发病机制，因此我们开发了创新的 原代细胞培养模型，以确定JCPyV感染所需的细胞因子。两个集成的特定 在本研究项目中提出的目的是：1)表征介导JCPyV进入和 原代细胞类型的感染，以及2)阐明持续型和裂解型JCPyV的细胞类型依赖性差异 感染。这项研究将加强我们对病毒-宿主细胞相互作用如何影响疾病的理解 结果，并将成为开发抗病毒治疗的平台。通过这项工作，细胞 JCPyV进入原代细胞类型所需的因素将通过功能丧失和获得来表征 使用基于细胞的分析的方法。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依赖的方式改变基因表达以确定途径 与JCPyV的致病机制和致命性疾病结局有关。这种组合方法利用了新的 开发了JCPyV感染的原代细胞模型，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在 了解JCPyV的生物学知识，可以阐明新的抗病毒靶点或为实验使用提供理论依据 市场上用于预防或治疗致命疾病PML的治疗方法。从这项研究中获得的发现也将 为其他致病病毒的进入和信号网络提供更广泛的见解，如冠状病毒、 并提高我们对癌症等其他疾病中细胞信号调节失调的理解。