Molecular Pathogenesis of Ovine Pulmonary Adenocarcinoma: Host Genetics and Age as Determinants of Disease Progression

绵羊肺腺癌（OPA）是一种由绵羊Jaagsiekte逆转录病毒（JSRV）引起的绵羊肺部肿瘤。OPA是英国和欧洲这种动物最重要的病毒性疾病之一（例如，OPA是第一只克隆的大型哺乳动物多莉死亡的原因）。JSRV通过表达一种蛋白质（包膜）诱导肺肿瘤，这种蛋白质刺激肺中的一些细胞，称为II型肺细胞和Clara细胞，使其不受控制地增殖。JSRV属于逆转录病毒家族。与任何其他病毒（如流感病毒）一样，JSRV从受感染宿主向未受感染宿主水平传播，因此被称为“外源性”逆转录病毒。有趣的是，绵羊的DNA中也有“内源性”逆转录病毒。这是因为逆转录病毒在其生命周期中，将其遗传物质插入细胞自身的DNA中。在进化过程中，一些逆转录病毒已经定居在所有动物物种的DNA中，在那里它们与正常基因共存。内源性逆转录病毒通常是“良性”病毒，不会造成任何伤害。因此，绵羊可以被一种有害的“外源性”病毒（JSRV）感染，同时它们的基因组中有大约27种不同的内源性“良性”病毒（enjsrv），这些病毒与JSRV高度相关。enjsrv可以通过阻断后者的复制来保护绵羊免受JSRV感染。有趣的是，我们最近发现27种enjsrv病毒中至少有8种只存在于某些羊/羊品种中。在这个提议中，我们将研究为什么感染JSRV在一些羊中导致肿瘤，而在另一些羊中却没有。我们的假设是：(i)羔羊最容易感染OPA，因为它们的肺细胞更容易被JSRV感染；（ii）一些绵羊中良性enjsrv的存在可以保护它们免受毒性JSRV的感染。通过完成拟议的工作，我们将能够将我们的发现转化为实践，为最易受JSRV感染和疾病进展的动物提供羊群管理建议。因此，该提案与BBSRC战略高度相关，并将提高英国农业系统的可持续性。

Ovine pulmonary adenocarcinoma (OPA) is a lung tumour of sheep caused by a virus known as Jaagsiekte sheep retrovirus (JSRV). OPA is one of the most important viral diseases of this animal species in the United Kingdom and Europe (OPA was for example the cause of death of Dolly, the first large mammal cloned). JSRV induces lung tumour by the expression of one of its proteins (the envelope) that stimulates some cells in the lungs, called type II pneumocytes and Clara cells, to proliferate without control. JSRV belongs to a family of viruses known as retroviruses. JSRV is transmitted from infected to uninfected host horizontally as any other virus (e.g. flu virus) and is therefore called an 'exogenous' retrovirus. Interestingly, sheep have also 'endogenous' retroviruses in their DNA. This is because retroviruses, during their life cycle, insert their genetic material in the cell's own DNA. During evolution, some retroviruses have colonized the DNA of all animal species where they co-exist with normal genes. Endogenous retroviruses are in general 'benign' viruses that do not cause any harm. Thus, sheep can be infected by a harmful 'exogenous' virus (JSRV) and at the same time they have ~27 different endogenous 'benign' viruses (enJSRVs) in their genome that are highly related to JSRV. enJSRVs can protect sheep against JSRV infection by blocking the replication of the latter. Interestingly, we have recently discovered that at least 8 of the 27 enJSRVs viruses are present only in some sheep/ sheep breeds. In this proposal we will study why infection with JSRV leads to tumor in some sheep but not in others. Our hypothesis is that (i) lambs are most susceptible to OPA because their lung cells can be infected more easily by JSRV and (ii) that the presence of benign enJSRVs in some sheep protects them against the virulent JSRV. By completing the proposed work we will be able to transfer our findings into practice by offering flock management advice on the most susceptible animals to JSRV infection and disease progression. Thus, this proposal is highly relevant to BBSRC strategy and will improve the sustainability of the UK farming system.