Gamma-herpesvirus infection of dendritic cells

描述(申请人提供)：伽玛疱疹病毒，如爱泼斯坦-巴尔病毒(EBV)和卡波西肉瘤相关疱疹病毒(KSHV)是在宿主中建立终身潜伏期的致癌病毒。这些重要的人类病原体与淋巴增生性疾病和许多恶性肿瘤有关，特别是在有获得性或遗传性免疫缺陷的人中。伽马疱疹病毒具有高度的物种特异性，因此小鼠疱疹病毒68(MHV-68)提供了一个很好的小动物模型来解决宿主的基本免疫学问题。MHV-68和KSHV都是γ-2型疱疹病毒，具有重要的生物学相似性，包括在体外缺乏明显的B细胞转化活性，以及在宿主内感染髓系细胞、巨噬细胞和树突状细胞的能力。在目前的方案中，我们将利用这一相关的小鼠模型，研究伽玛疱疹病毒与树突状细胞之间的相互作用。树突状细胞是启动和调节T细胞免疫的特化抗原提呈细胞，在病毒感染的应答中起着关键作用。伽玛2型疱疹病毒编码许多基因，这些基因的功能是破坏抗原提呈、细胞迁移、细胞周期和细胞凋亡。我们的假设是，MHV-68以树突状细胞为靶点，干扰其功能能力或利用其功能。这在早期发病机制中可能是至关重要的，并有助于感染的建立。我们的研究将通过追求以下具体目标来解决这些问题：1)确定MHV-68对树突状细胞功能的改变程度。2)探讨MHV-68在宿主感染早期对树突状细胞功能的影响。3)探讨急性感染过程中树突状细胞感染对MHV-68免疫逃避的影响。预计这项建议中收集的信息将有助于我们了解伽马疱疹病毒的免疫控制和逃避。我们的问题对于理解如何对破坏树突状细胞功能的病毒产生免疫力，以及更好地设计针对伽马疱疹病毒的免疫疗法也是至关重要的。

DESCRIPTION (provided by applicant): gamma-Herpesviruses such as Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV) are oncogenic viruses that establish life-long latency in the host. These important human pathogens are associated with lymphoproliferative disorders and numerous malignancies, particularly in individuals with acquired or inherited immunodeficiencies. gamma-Herpesviruses are extremely species specific, thus murine gamma-herpesvirus 68 (MHV-68) provides an excellent small animal model to address basic immunological questions in the host. MHV-68 and KSHV are gamma2-herpesviruses and share important biological similarities, including the lack of obvious B cell transforming activity in vitro and the capacity to infect cells of myeloid origin, macrophages and dendritic cells, in the host. In the current proposal, we will exploit this relevant mouse model, to study the interaction between gamma-herpesviruses and dendritic cells. Dendritic cells are specialized antigen presenting cells that initiate and modulate T cell immunity, playing a critical role in the response to viral infections. gamma2-Herpesviruses encode numerous genes that function to impair antigen presentation, cellular migration, cell cycle and apoptosis. Our hypothesis is that MHV-68 targets dendritic cells to interfere with their functional ability or exploit their function. This may be crucial during early pathogenesis and contribute to the establishment of infection. Our studies will address these issues by pursuing the following specific aims: 1) To determine to what extent MHV-68 alters dendritic cell function. 2) To determine the impact of MHV-68 on the functional capacity of dendritic cells early during infection in the host. 3) To determine the impact of dendritic cell infection on MHV-68 immune evasion during acute infection. It is anticipated that the information gathered in this proposal will contribute to our understanding of the immune control and evasion of gamma-herpesviruses. Our questions are also critical to understanding how immunity is generated against viruses that subvert dendritic cell function, and for the better design of immunotherapies against gamma-herpesviruses.