Characterization of an animal model of chronic infection and disease

描述（由申请方提供）：γ疱疹病毒引起终身感染，并与各种疾病相关，特别是在免疫缺陷宿主中。人类γ疱疹病毒、爱泼斯坦巴尔病毒（EBV）和卡波西肉瘤相关病毒与许多恶性肿瘤相关，包括淋巴组织增生性疾病和淋巴瘤。鼠γ疱疹病毒-68与人γ疱疹病毒在遗传和生物学上是保守的，并且自然感染小鼠。我们最近发现，对细胞因子干扰素-γ无反应的小鼠感染γ-疱疹病毒-68导致肺部显著的血管中心性炎症，并在感染后5至9个月内进展为坦率淋巴瘤。这些个体的炎性病变富含B细胞和病毒感染的细胞，并且所产生的淋巴瘤主要由病毒感染的B细胞组成。这些病变和淋巴瘤与慢性病毒感染（包括EBV）相关的人肺淋巴瘤具有惊人的相似性。在这个试点研究的建议中，我们的目标是扩展我们对这些免疫缺陷相关淋巴瘤的初步表征。首先，我们建议最后确定干扰素-γ无反应小鼠的完整队列的基本特征，这些小鼠模拟治疗或感染γ疱疹病毒长达一年。我们将确定无瘤生存期、肿瘤细胞类型和淋巴瘤细胞的病毒感染状态。其次，我们将描述这些免疫缺陷相关淋巴瘤的克隆性、细胞类型组成和病毒基因表达。我们这些研究的长期目标是开发免疫缺陷相关淋巴瘤发生的小动物模型，阐明慢性感染相关恶性肿瘤的分子机制，获得对类似人类肿瘤的新见解，并促进转化研究。公共卫生相关性：慢性感染和疾病动物模型的表征。慢性病毒感染和免疫缺陷可导致不同的疾病结果。这项初步研究将提供一个有价值的模型系统，以进一步了解人类肺淋巴瘤。这项与慢性病毒感染相关的炎症和淋巴瘤研究将为未来的研究奠定基础，以确定这些肿瘤的遗传和环境风险，肿瘤进展的病毒和宿主贡献者，以及成功治疗可能被破坏的关键途径。

DESCRIPTION (provided by applicant): Gammaherpesviruses cause lifelong infection and are associated with various diseases, particularly in immune deficient hosts. The human gammaherpesviruses, Epstein Barr virus (EBV) and Kaposi's sarcoma associated virus, are associated with a number of malignancies, including lymphoproliferative disease and lymphomas. Murine gammaherpesvirus-68 is a genetically and biologically conserved with the human gammaherpesviruses, and naturally infects mice. We recently identified that gammaherpesvirus-68 infection of mice unresponsive to the cytokine interferon-gamma results in significant angiocentric inflammation in the lung with variable progression to frank lymphoma within five to nine months of infection. The inflammatory lesions in these individuals are rich in B cells and in virus-infected cells, and the resulting lymphomas are composed primarily of virus-infected B cells. These lesions and lymphomas bear striking similarity to human pulmonary lymphomas associated with chronic virus infection (including EBV). In this proposal for a pilot study, our goal is to extend our initial characterization of these immunodeficiency-associated lymphomas. First, we propose to finalize basic characterization of full cohorts of interferon-gamma unresponsive mice that are mock treated or infected with gammaherpesvirus for up to one year. We will determine tumor-free survival, tumor cell type and virus infection status of lymphoma cells. Second, we will characterize clonality, cell type composition, and virus gene expression of these immunodeficiency- associated lymphomas. Our long-term goal for these studies is the development of a small animal model for immunodeficiency-associated lymphomagenesis that will elucidate the molecular mechanisms that contribute to chronic infection-associated malignancies, to gain new insights into similar human neoplasms and facilitate translational studies. PUBLIC HEALTH RELEVANCE: Characterization of an animal model of chronic infection and disease. Chronic virus infection and immune defects can lead to variable disease outcomes. This pilot study will provide a valuable model system to further our understanding of human pulmonary lymphomas. This study of inflammation and lymphoma associated with chronic virus infection will set the stage for future studies to define the genetic and environmental risks for these tumors, the viral and host contributors to tumor progression, and the critical pathways that could be disrupted for successful therapies.