Hamster Model of SV40 Infection and Disease

SV40 感染和疾病的仓鼠模型

• 批准号: 8309872
• 负责人: JANET S BUTEL
• 金额: $ 30.9万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8309872
• 关键词: Acute; Affect; Antibody Formation; Biological Assay; Biology; Cancer Etiology; Chronic; Data; Development; Disease; Disease Outcome; Event; Gene Expression; Goals; Hamsters; Health; Human; Immune response; Incidence; Infection; Interleukin-10; Kidney Diseases; Laboratories; Lead; Lymphocyte; Lymphoid Cell; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; MicroRNAs; Modeling; Neurologic; Nucleic Acid Regulatory Sequences; Outcome; Pathogenesis; Pattern; Play; Polyomavirus; Polyomavirus Infections; Reagent; Research; Risk; Role; Route; Simian virus 40; Staging; Therapeutic; Tissues; Ultrasonography; Viral; Viral Genes; Viral Load result; Viral Pathogenesis; Viral Tumor Antigens; Virus; Virus Diseases; Work; carcinogenesis; cell immortalization; cell type; cytokine; defined contribution; design; genetic variant; in vivo; innovation; insight; new therapeutic target; novel; prevent; programs; success; tumor; tumor progression; viral DNA; virus genetics; virus host interaction

DESCRIPTION (provided by applicant): Human cancer viruses establish persistent infections in their hosts. We hypothesize that the risk of viral induced cancer is dependent on early events in virus-host interactions that lead to the establishment of persistent viral infections with elevated viral loads. It is now recognized that polyomavirus SV40 can cause human infections and can be detected in selected human cancers. Early events during SV40 infections in vivo that lead to cancer development have not been explored. This project will utilize the hamster model to identify and characterize virus genetic factors and host responses involved in the pathogenesis of SV40 infections and subsequent carcinogenesis. Specific Aim 1 will identify viral genetic factors that influence patterns of SV40 acute and chronic infections in hamsters. Wild-type SV40 and matched constructs that differ in SV40 strain-specific regions will examine the influence of the regulatory region, the T-antigen variable domain, and SV40 microRNA on establishment of acute and chronic infections in vivo and on viral loads. Specific Aim 2 will define the contribution of viral genetic factors to the development of SV40-mediated malignant disease. Tumor incidences in hamsters exposed to SV40 genetic variants by different routes of administration will be related to the establishment and viral loads of acute and chronic SV40 infections. Early-stage lymphomas will be detected using noninvasive ultrasound and changes in viral expression during tumor progression analyzed. Specific Aim 3 will determine SV40 effects on lymphoid cells and on host responses to infection. The interactions of SV40 with cultured hamster lymphoid cells will be defined with respect to viral expression and cell immortalization. Host responses involving cytokine expression and antibody production will be evaluated in the context of establishment and outcome of virus infections. The potential roles of SV40 microRNA and of cytokine IL-10 in modulating host responses to SV40 infections will be explored. The innovative design of this project will yield significant new understandings of the biology of SV40 infections and of mechanisms relevant to SV40 involvement in human malignancies. New insights into early events in viral pathogenesis will be applicable to polyomavirus infections in humans and may identify novel targets for the development of polyomavirus therapeutics. PUBLIC HEALTH RELEVANCE: Polyomaviruses cause cancer, kidney disease, and neurologic disease. This proposal will identify the interactions of virus genetic factors and host responses that lead to chronic viral infections and subsequent disease development. This project will provide new understandings of mechanisms relevant to polyomaviruses and human cancer and may identify novel targets for therapeutics to treat polyomavirus infections and prevent disease.

描述（由申请方提供）：人癌病毒在其宿主中建立持续感染。我们假设病毒诱发癌症的风险取决于病毒-宿主相互作用中的早期事件，这些事件导致病毒载量升高的持续性病毒感染的建立。现在认识到，多瘤病毒SV 40可以引起人类感染，并且可以在选定的人类癌症中检测到。尚未探索体内SV 40感染期间导致癌症发展的早期事件。该项目将利用仓鼠模型来鉴定和表征参与SV 40感染发病机制和随后致癌作用的病毒遗传因素和宿主反应。具体目标1将确定影响仓鼠SV 40急性和慢性感染模式的病毒遗传因素。野生型SV 40和在SV 40毒株特异性区域中不同的匹配构建体将检查调节区、T抗原可变结构域和SV 40 microRNA对体内急性和慢性感染的建立以及对病毒载量的影响。具体目标2将定义病毒遗传因素对SV 40介导的恶性疾病发展的贡献。通过不同给药途径暴露于SV 40遗传变异体的仓鼠中的肿瘤发生率将与急性和慢性SV 40感染的建立和病毒载量相关。将使用非侵入性超声检测早期淋巴瘤，并分析肿瘤进展期间病毒表达的变化。特定目标3将确定SV 40对淋巴细胞和宿主对感染反应的影响。根据病毒表达和细胞永生化定义SV 40与培养仓鼠淋巴细胞的相互作用。涉及细胞因子表达和抗体产生的宿主应答将在病毒感染的建立和结果的背景下进行评价。将探讨SV 40 microRNA和细胞因子IL-10在调节宿主对SV 40感染反应中的潜在作用。该项目的创新设计将产生对SV 40感染的生物学和与SV 40参与人类恶性肿瘤相关的机制的重要新理解。对病毒发病机制中早期事件的新见解将适用于人类多瘤病毒感染，并可能为多瘤病毒治疗剂的开发确定新的靶点。公共卫生相关性：多瘤病毒可导致癌症、肾脏疾病和神经系统疾病。该提案将确定导致慢性病毒感染和随后疾病发展的病毒遗传因素和宿主反应的相互作用。该项目将提供对多瘤病毒和人类癌症相关机制的新理解，并可能确定治疗多瘤病毒感染和预防疾病的新靶点。

项目成果

Viral microRNA effects on pathogenesis of polyomavirus SV40 infections in syrian golden hamsters.

• DOI: 10.1371/journal.ppat.1003912
• 发表时间: 2014-02
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Zhang S;Sroller V;Zanwar P;Chen CJ;Halvorson SJ;Ajami NJ;Hecksel CW;Swain JL;Wong C;Sullivan CS;Butel JS
• 通讯作者: Butel JS