Proviral Roles of an Innate Immune Pathway

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。人类卡波西肉瘤相关疱疹病毒（KSHV）和爱泼斯坦-巴尔病毒与免疫功能低下患者的淋巴、上皮和内皮源性肿瘤有关。由于缺乏人体研究和缺乏允许的细胞系和动物模型，宿主免疫反应和KSHV和EBV的体内感染在很大程度上是未知的。小鼠3-疱疹病毒68 （3HV68）是KSHV和EBV密切相关的病毒，感染小鼠，在肺中复制到更高的滴度，并在脾脏中建立持续的潜伏感染，为描述整个免疫反应和体内病毒感染提供了一个极好的易处理的动物模型。在病毒感染时，宿主的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。利用3HV68作为KSHV和EBV的模型，我们最近发现3HV68劫持了一条先天免疫途径，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激活宿主先天免疫信号通路的分子机制，从而促进Aim 1中的病毒转录激活，并破坏Aim 2中的抗病毒细胞因子产生。此外，我们将在Aim 3中描述激活先天免疫途径的病毒-宿主相互作用。总之，本研究将阐明一种新的机制，即3HV68感染激活宿主先天免疫信号通路，使病毒转录和禁用宿主细胞因子的产生，从而极大地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。

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.!