Pathogenesis of enzootic nasal tumor virus (ENTV)

逆转录病毒诱导肿瘤的动物模型为我们目前对致癌过程的理解提供了许多基础。与分泌性呼吸道上皮细胞肿瘤相关的两种经济上重要的逆转录病毒是绵羊Jaagsiekte绵羊逆转录病毒（JSRV）和绵羊和山羊的鼻部地方性肿瘤病毒（ENTV）。虽然JSRV和ENTV是高度相关的β逆转录病毒，它们利用相同的细胞表面受体进入细胞，但它们具有不同的肿瘤诱导能力。JSRV转化肺泡II型肺细胞，而ENTV转化鼻上皮细胞。其原因尚不清楚。本研究提出了这样一种假设，即在羊宿主中诱导组织特异性肿瘤形成要么是长末端重复序列（LTR）细胞限制性活性的功能，要么是由于ENTV和JSRV需要一个辅助受体才能进入，而亲和力或辅助受体使用的差异决定了细胞的趋向性。为了解决这些假设，将构建一个ENTV的分子克隆并用于产生感染性病毒进行体内研究。在证明ENTV是地方性鼻腺癌的病原后，通过JSRV和ENTV之间的遗传物质交换产生的一系列嵌合病毒将被构建并用于绘制组织特异性肿瘤形成的遗传元件。具体地说，这些实验将讨论辅助受体使用和LTR活性受限的可能性。预计本研究项目将有助于我们对病毒诱导的癌症的理解，揭示逆转录病毒进入的潜在新机制，并阐明分泌性呼吸道上皮细胞肿瘤转化的机制。目前，没有可用于ENTV的死前诊断工具。因此，建立ENTV感染的动物模型可以分析ENTV的细胞和组织分布，并随后确定用于ENTV核酸扩增的敏感模板源。然后可以开发基于pcr的诊断分析方法，并在旨在从加拿大绵羊和山羊群中根除ENTV的检测和清除计划中实施。

Animal models of retrovirus-induced tumors have provided us with much of the foundation for our current understanding of the oncogenic process. Two economically important retroviruses associated with tumors of secretory respiratory epithelial cells are the Jaagsiekte sheep retrovirus (JSRV) and Enzootic nasal tumor virus (ENTV) of sheep and goats. While JSRV and ENTV are highly related betaretroviruses that utilize the same cell surface receptor for virus entry, they have distinct tumor-inducing capabilities. JSRV transforms alveolar type II pneumocytes, while ENTV transforms nasal epithelial cells. The reason for this is not known. This proposal addresses the hypothesis that induction of tissue-specific tumor formation in the ovine host is either a function of cell-restricted activity of the long terminal repeat (LTR) or due to the fact that ENTV and JSRV require a coreceptor for virus entry and differences in affinity or coreceptor usage determines cellular tropism. To address these hypotheses, a molecular clone of ENTV will be constructed and used to generate infectious virus for in vivo studies. Upon demonstration that ENTV is the etiologic agent of enzootic nasal adenocarcinoma, a series of chimeric viruses generated via the exchange of genetic material between JSRV and ENTV will be constructed and used to map genetic elements responsible for tissue-specific tumor formation. Specifically, the potential for coreceptor usage and restricted LTR activity will be addressed in these experiments. It is anticipated that this research program will contribute to our understanding of virally-induced cancers, uncover a potentially novel mechanism for retrovirus entry, and shed light on the mechanisms governing neoplastic transformation of secretory respiratory epithelial cells. Currently, no antemortem diagnostic tools are available for ENTV. Therefore, creating an animal model for ENTV infection allows for analysis of the cellular and tissue distribution of ENTV and subsequent identification of sensitive template sources for ENTV nucleic acid amplification. PCR-based diagnostic assays could then be developed and implemented in test and removal programs aimed at eradicating ENTV from Canadian sheep and goat flocks.