Project 1 - Virus-Host Interactions in Gammaherpesvirus Pathogenesis

人类伽玛疱疹病毒（ghv）、爱泼斯坦-巴尔病毒（EBV）和卡波西肉瘤相关疱疹病毒（KSHV）是DNA肿瘤病毒，可在宿主淋巴细胞和其他细胞类型中建立终身慢性感染。通过表达改变正常细胞信号通路和抵抗宿主免疫反应的病毒基因产物，ghv使慢性感染的宿主处于多种恶性肿瘤的危险之中。由于它涉及到COBRE的主题，即确定微生物毒力因子对宿主炎症和免疫反应的影响，因此本项目中描述的实验的总体目标是更好地确定ghv对抗宿主先天防御机制的机制，从而成功定殖宿主。这一目标的核心是利用小鼠γ疱疹病毒-68 (MHV68)，这是一种自然发生的啮齿动物病原体，与EBV和KSHV有遗传关系，概括了人类GHV感染的关键方面，作为一种可处理的小动物模型，以确定体内病毒-宿主相互作用。扩展我们已发表的和初步的数据，目前的建议特别寻求了解MHV68潜伏期相关核抗原（mLANA）的功能，mLANA是一种假定的病毒转录抑制蛋白，作为抗病毒转录途径或干扰素α / β (IFN-I)信号激活的细胞免疫反应的关键调节剂，否则会限制GHV感染。这项工作将在三个综合但独立的特定目标下完成：(1)确定ifn -l介导的粘膜屏障对GHV感染的控制，(2)阐明mlana介导的MHV68发病机制中的转录控制作用，(3)确定mlana -干扰素调节因子3 （IRF-3）在MHV68感染中的相互作用。提出的实验具有广泛的意义，因为它解决了我们对GHV发病机制的理解中的两个关键空白：病毒性疾病决定因素在GHV感染成功中的作用以及GHV与宿主先天免疫反应途径的相互作用。此外，通过推进对宿主免疫反应性质的理解，这对所有传染病都是至关重要的，拟议的实验也可能与由多种不相关的细胞内病原体引起的疾病相关。

The human gammaherpesviruses (GHVs) Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are DNA tumor viruses that establish lifelong chronic infections of host lymphocytes and other cell types. Through the expression of viral gene products that alter normal cellular signaling pathways and counteract host immune responses, GHVs place the chronically infected host at risk for numerous malignancies. As it relates to the COBRE theme of defining the impact of microbial virulence factors on host inflammatory and immune responses, the overall objective of experiments described in this project is to better define mechanisms by which GHVs counteract innate host defense mechanisms in order to successfully colonize a host. Central to this objective is the utilization of murine gammaherpesvirus-68 (MHV68), a naturally occurring rodent pathogen that is genetically related to EBV and KSHV and recapitulates key aspects of human GHV infection as a tractable small-animal model to define the virus-host interaction in vivo. Extending our published and preliminary data, the current proposal specifically seeks to understand functions of the MHV68 latency-associated nuclear antigen (mLANA), a putative viral transcriptional repressor protein, as a critical modulator of antiviral transcriptional pathways or cellular immune responses activated by interferon alpha/Beta (IFN-I) signaling that would otherwise restrict GHV infection. This work will be accomplished in three integrated but independent specific aims: (1) define IFN-l-mediated control of GHV infection at mucosal barriers, (2) elucidate roles for mLANA-mediated transcriptional control in MHV68 pathogenesis, and (3) define mLANA-interferon regulatory factor 3 (IRF-3) interactions in MHV68 infection. The proposed experiments hold broad significance by addressing two critical gaps in our understanding of GHV pathogenesis: the functions of viral disease determinants in the success of GHV infection and the interactions of GHV with host innate immune response pathways. Moreover, by advancing understanding of the nature of host immune responses, which is fundamentally important to all infectious diseases, the proposed experiments may also hold relevance for diseases caused by diverse and unrelated intracellular pathogens.