Proviral Roles of an Innate Immune Pathway

描述(申请人提供)：疱疹病毒在人类中普遍存在，它们与多种恶性肿瘤有关。人类卡波西肉瘤相关疱疹病毒(KSHV)和爱泼斯坦-巴尔病毒(Epstein-Barr Virus)与免疫受损患者的淋巴样、上皮性和内皮源性肿瘤有关。由于缺乏人类研究，缺乏可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。小鼠3-疱疹病毒68(3HV68)与KSHV和EBV关系密切，可感染小鼠，在肺部复制到较高滴度，并在脾建立持续潜伏感染，为描述整个免疫反应和体内病毒感染提供了一个很好的易于处理的动物模型。在病毒感染后，宿主的天然免疫途径经常被激活，以诱导产生抗病毒的炎性细胞因子和干扰素。利用3HV68作为KSHV和EBV的模型，我们最近发现3HV68劫持了一条先天性免疫途径，以促进病毒的裂解复制和阻止抗病毒细胞因子的产生。因此，我们将研究3HV68激活宿主天然免疫信号通路以促进AIM 1中病毒转录激活和颠覆AIM 2中抗病毒细胞因子产生的分子机制。此外，我们还将描述病毒与宿主之间的相互作用，激活AIM 3中的天然免疫途径。总之，本研究将阐明3HV68感染激活宿主天然免疫信号通路以启动病毒转录和抑制宿主细胞因子产生的新机制，从而极大地扩展我们目前的免疫颠覆范式。这项研究的发现将促进我们对宿主激活和病毒利用先天免疫反应的理解，并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天然免疫途径被用来促进病毒感染的分子机制，并描绘激活天然免疫途径的病毒与宿主的相互作用。因此，本研究将促进我们对病原体免疫利用、宿主先天免疫反应和病毒致病机制的了解。我们的研究结果将重塑我们对“抗病毒先天免疫”的看法，为使用人类致癌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。

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.!