Proviral Roles of an Innate Immune Pathway

先天免疫途径的前病毒作用

基本信息

批准号：
8184241
负责人：
Pinghui Feng
金额：
$ 40.75万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-02 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8184241
关键词：
Acute Animal Model Antiviral Agents Biochemical Biological Process Cell Line Complex Cultured Cells Cytokine Activation DNA Viruses Data Epithelial Fibroblasts Future Genes Genetic Transcription Glean Goals Herpesviridae Human Human Herpesvirus 4 Human Herpesvirus 8 Immune Immune response Infection Infectious Diseases Research Inflammatory Interferons Laboratories Lead Lung Malignant Neoplasms Mediating Mitochondria Modeling Molecular Mus Mutation Analysis Natural Immunity Outcome Pathway interactions Patients Phosphorylation Phosphotransferases Production Proteins RNA Recombinants Regulation Research Role Shapes Signal Pathway Signal Transduction Spleen TBK1 gene Testing Therapeutic Transcription Coactivator Transcriptional Activation Tretinoin Vaccine Design Viral Viral Pathogenesis Virion Virus Virus Diseases Work arm cytokine dimer gammaherpesvirus immune activation improved in vivo insight latent persistent infection lymphoid neoplasm lytic replication mutant novel pathogen prevent research study sensor tumorigenic ubiquitin-protein ligase virus host interaction

项目摘要

DESCRIPTION (provided by applicant): Herpesviruses are ubiquitous in humans and they have been implicated in diverse malignancies. Human Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus are associated with tumors of lymphoid, epithelial, and endothelial origin in immuno-compromised patients. Due to a paucity of human studies and lack of permissive cell lines and animal models, host immune responses and in vivo infection of KSHV and EBV are largely unknown. Being closely-related KSHV and EBV, murine 3- herpesvirus 68 (3HV68) infects mice, replicates to higher titers in the lung and establishes persistent latent infection in the spleen, providing an excellent tractable animal model to delineate the entire immune responses and viral infection in vivo. Upon viral infection, host innate immune pathways are often activated to induce the production of antiviral inflammatory cytokines and interferons. Using 3HV68 as a model for KSHV and EBV, we have recently discovered that 3HV68 hijacks an innate immune pathway to promote viral lytic replication and to prevent antiviral cytokine production. Thus, we will investigate the molecular mechanisms by which 3HV68 deploys to activate the host innate immune signaling pathway to promote viral transcriptional activation in Aim 1 and to subvert antiviral cytokine production in Aim 2. Furthermore, we will delineate the virus-host interactions that activate the innate immune pathway in Aim 3. Collectively, this study will elucidate a novel mechanism whereby 3HV68 infection activates a host innate immune signaling pathway to enable viral transcription and disable host cytokine production, thereby greatly expanding our current paradigm of immune subversion. Findings gleaned from this study will advance our understanding of host activation and viral exploitation of innate immune responses, and potentially guide our future efforts in vaccine design and antiviral therapeutics to treat malignancies associated with human KSHV and EBV. PUBLIC HEALTH RELEVANCE: The aims of this study are to investigate the molecular mechanisms by which a host innate immune pathway is exploited to facilitate viral infection and to delineate the virus-host interactions that activate the innate immune pathway. Thus, this study will advance our understanding of pathogen immune exploitation, host innate immune responses, and viral pathogenesis. Findings from our study will re-shape our view of "antiviral innate immunity", provide an animal model for studies using human tumorigenic herpesviruses, and also potentially guide future efforts to treat herpesvirus-associated malignancies.!

描述（由申请人提供）：疱疹病毒在人类中普遍存在，并且与多种恶性肿瘤有关。人卡波西肉瘤相关疱疹病毒 (KSHV) 和 Epstein-Barr 病毒与免疫功能低下患者的淋巴、上皮和内皮来源的肿瘤有关。由于人类研究的缺乏以及缺乏允许的细胞系和动物模型，KSHV 和 EBV 的宿主免疫反应和体内感染在很大程度上是未知的。鼠 3-疱疹病毒 68 (3HV68) 与 KSHV 和 EBV 密切相关，它会感染小鼠，在肺部复制到更高滴度，并在脾脏中建立持续的潜伏感染，为描述整个免疫反应和病毒感染提供了一个极好的易处理的动物模型体内。病毒感染后，宿主先天免疫途径通常被激活，诱导抗病毒炎症细胞因子和干扰素的产生。使用 3HV68 作为 KSHV 和 EBV 的模型，我们最近发现 3HV68 劫持了先天免疫途径，以促进病毒裂解复制并阻止抗病毒细胞因子的产生。因此，我们将研究 3HV68 部署激活宿主先天免疫信号通路以促进目标 1 中病毒转录激活并破坏目标 2 中抗病毒细胞因子产生的分子机制。此外，我们将描述激活宿主先天免疫信号通路的病毒-宿主相互作用目标 3 中的先天免疫途径。总的来说，这项研究将阐明一种新机制，即 3HV68 感染激活宿主先天免疫信号传导途径，以实现病毒转录并禁用宿主细胞因子生产，从而极大地扩展了我们当前的免疫颠覆范式。这项研究的结果将增进我们对宿主激活和病毒利用先天免疫反应的理解，并有可能指导我们未来在疫苗设计和抗病毒疗法方面的努力，以治疗与人类 KSHV 和 EBV 相关的恶性肿瘤。公共卫生相关性：本研究的目的是研究利用宿主先天免疫途径促进病毒感染的分子机制，并描述激活先天免疫途径的病毒与宿主的相互作用。因此，这项研究将增进我们对病原体免疫利用、宿主先天免疫反应和病毒发病机制的理解。我们的研究结果将重塑我们对“抗病毒先天免疫”的看法，为使用人类致瘤性疱疹病毒的研究提供动物模型，并有可能指导未来治疗疱疹病毒相关恶性肿瘤的努力。