Proviral Roles of an Innate Immune Pathway

描述（由申请方提供）：疱疹病毒在人类中普遍存在，并与多种恶性肿瘤有关。人卡波西肉瘤相关疱疹病毒（KSHV）和EB病毒与免疫功能低下患者的淋巴、上皮和内皮来源的肿瘤相关。由于缺乏人体研究和缺乏允许的细胞系和动物模型，宿主免疫应答和KSHV和EBV的体内感染在很大程度上是未知的。鼠3型疱疹病毒68（3 HV 68）与KSHV和EBV密切相关，可感染小鼠，在肺内复制至较高滴度，并在脾内建立持续潜伏感染，为描述体内免疫反应和病毒感染提供了一个良好的动物模型。 在病毒感染后，宿主先天免疫途径通常被激活以诱导抗病毒炎性细胞因子和干扰素的产生。使用3 HV 68作为KSHV和EBV的模型，我们最近发现3 HV 68劫持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产生。因此，我们将研究3 HV 68部署激活宿主先天免疫信号传导途径以促进Aim 1中的病毒转录激活和破坏Aim 2中的抗病毒细胞因子产生的分子机制。此外，我们将描绘的病毒宿主的相互作用，激活先天免疫途径的目标3。总的来说，这项研究将阐明一种新的机制，即3 HV 68感染激活宿主先天免疫信号传导途径，使病毒转录和禁用宿主细胞因子的生产，从而大大扩展了我们目前的免疫颠覆范式。从这项研究中收集的发现将促进我们对宿主激活和先天免疫反应的病毒利用的理解，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：本研究的目的是探讨宿主先天免疫途径被利用以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-宿主相互作用。因此，这项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理解。我们的研究结果将重新塑造我们对“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.!