Gamma-herpesvirus infection of dendritic cells

描述（由申请人提供）：γ -疱疹病毒，如eb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，特别是在获得性或遗传性免疫缺陷的个体中。γ -疱疹病毒具有极强的物种特异性，因此小鼠γ -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，以及在宿主体内感染髓系细胞、巨噬细胞和树突状细胞的能力。在目前的提议中，我们将利用这一相关的小鼠模型，来研究γ -疱疹病毒和树突状细胞之间的相互作用。树突状细胞是一种特殊的抗原呈递细胞，可启动和调节T细胞免疫，在病毒感染应答中起着关键作用。γ - 2疱疹病毒编码许多基因，这些基因的功能是损害抗原呈递、细胞迁移、细胞周期和细胞凋亡。我们的假设是MHV-68以树突状细胞为目标，干扰它们的功能或利用它们的功能。这可能在早期发病过程中至关重要，并有助于感染的建立。我们的研究将通过以下具体目标来解决这些问题：1)确定MHV-68改变树突状细胞功能的程度。2)确定MHV-68在宿主感染早期对树突状细胞功能能力的影响。3)确定树突状细胞感染对急性感染时MHV-68免疫逃逸的影响。预计本提案中收集的信息将有助于我们对γ -疱疹病毒的免疫控制和逃避的理解。我们的问题对于理解如何产生针对破坏树突状细胞功能的病毒的免疫力，以及更好地设计针对γ -疱疹病毒的免疫疗法也至关重要。

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.