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

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

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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）：疱疹病毒在人类中无处不在，并且与多种恶性肿瘤有关。人类Kaposi与肉瘤相关的疱疹病毒（KSHV）和Epstein-Barr病毒与免疫受损患者的淋巴样，上皮和内皮起源有关。由于缺乏人类研究以及缺乏允许的细胞系和动物模型，宿主的免疫反应以及KSHV和EBV体内感染的体内感染在很大程度上尚不清楚。与密切相关的KSHV和EBV密切相关，鼠3-疱疹病毒68（3HV68）感染了小鼠，复制到肺部较高的滴度，并在脾脏中建立了持续的潜在感染，从而提供了一种极好的拖延动物模型，以划定整个免疫反应和ViraL Inturection in Vivo中的整个免疫反应和病毒感染。病毒感染后，通常会激活宿主先天免疫途径，以诱导抗病毒炎性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劫持了一种先天的免疫途径来促进病毒裂解复制并防止抗病毒细胞因子产生。因此，我们将研究3HV68激活宿主先天免疫信号传导途径的分子机制，以促进目标1中的病毒转录激活，并在目标2中颠覆抗病毒细胞因子的产生。激活宿主先天免疫信号通路，以实现病毒转录并禁用宿主细胞因子的产生，从而大大扩展了我们当前的免疫颠覆范围。从这项研究中收集的发现将提高我们对宿主激活和对先天免疫反应的病毒剥削的理解，并有可能指导我们未来在疫苗设计和抗病毒治疗方面的努力，以治疗与人类KSHV和EBV相关的恶性肿瘤。公共卫生相关性：这项研究的目的是研究宿主先天免疫途径的分子机制，以促进病毒感染并描述激活先天免疫途径的病毒宿主相互作用。因此，这项研究将提高我们对病原体免疫剥削，宿主先天免疫反应和病毒发病机理的理解。我们研究中的发现将使我们对“抗病毒先天免疫”的看法，为使用人类肿瘤疱疹病毒的研究提供了一种动物模型，并有可能指导未来治疗与疱疹病毒相关的恶性肿瘤的努力。