The Molecular Biology of FMDV Replication: Towards New Methods of FMDV Disease Control.

我们最大的挑战之一将是满足日益增长的粮食需求，特别是在发展中世界以及对肉类产品需求不断上升的印度和中国等经济体。动物疾病对畜牧业的生产力有重大影响，保护动物福利将是最大限度提高粮食产量的主要组成部分。口蹄疫病毒(FMDV)是一种感染家养动物(牛、绵羊、山羊和猪)的动物病原体。它可能是已知的最具传染性的哺乳动物病毒，也是人们非常害怕的，因为这种病毒可以极其迅速地传播。这种病毒还可以引起长期的、明显的“持续”感染；它们很难在现场诊断，并使疾病控制复杂化。口蹄疫病毒还可以感染许多种类的野生动物，在非洲，野生动物的持续感染提供了一个可能感染家畜的重要蓄水池。口蹄疫病毒在全球范围内引起疾病，并通过进口受污染的动物和动物产品持续威胁英国农业。感染很少是致命的，但它可以对农场动物的生产力产生巨大影响。2001年的英国疫情造成了巨大的经济损失(数十亿英镑)，原因是贸易损失和对农业社区的影响。此外，通过宰杀受感染和高风险的动物来控制疾病是极具争议性的，也是不受欢迎的，并导致人们对“活体接种疫苗政策”的兴趣增强。疫苗通常有两种类型。第一种是灭活或“杀死”的病毒，它们不能感染宿主，但仍使免疫系统准备好，以防止以后的感染。第二种是被削弱或“减毒”的活病毒：它们确实会感染宿主，从而触发优越的免疫反应，但不足以致病。目前的口蹄疫疫苗只是“灭活型”疫苗。相比之下，对于密切相关的人类病毒脊髓灰质炎病毒，已使用减毒活疫苗有效控制疾病和传播，从而使全球根除脊髓灰质炎病毒指日可待。目前口蹄疫“灭活”疫苗的有效性受到许多因素的限制，迫切需要开发新的控制措施：因此，我们希望开发新的“减毒”疫苗，这是本研究的目标之一。要安全地做到这一点，需要详细了解口蹄疫病毒与其宿主之间的复杂相互作用。我们提出的研究将为口蹄疫病毒如何与其宿主细胞相互作用实现快速复制或建立持续感染提供新的见解。我们将利用这些信息来提高疫苗的有效性和安全性。第一种策略是利用现代分子生物学改变病毒，制造出既能保护动物又不会导致衰弱疾病的新病毒--即所谓的减毒活病毒。第二种策略是利用病毒如何在细胞中生长的知识来制造一种新型病毒，这种病毒只能在我们也将创造的特殊的“辅助”细胞中生长。这种病毒将不能在动物体内生长并导致疾病。这将使传统的“灭活疫苗”生产过程更加安全。任何一种方法的成功都将刺激常规使用疫苗在全球控制口蹄疫病毒。从长远来看，这可能会通过减少口蹄疫在全球的总体发病率而产生影响，在世界范围内具有巨大的经济和社会价值。我们认为，更好地控制口蹄疫对粮食安全至关重要，必须与新疫苗的开发或新的疫苗生产方法相结合，才能使这一政策有效。这就是我们研究的目的。

One of our biggest challenges will be to meet a growing demand for food, especially in the developing world and economies such as India and China where the demand for meat products is rising. Animal diseases have a major impact on the productivity of the livestock industry and safeguarding animal welfare will be a major component of maximising food production. Foot-and-mouth disease virus (FMDV) is an animal pathogen which infects domesticated animals (cattle, sheep, goats and pigs). It is probably the most contagious mammalian virus known and much feared as the virus can spread extremely rapidly. The virus can also cause long-term 'persistent' infections that are in apparent; they are difficult to diagnose in the field and complicate disease control. FMDV can also infect many species of wildlife, and in Africa persistent infections in wildlife provides an important reservoir that may infect domestic livestock.FMDV causes disease around the globe and is a continual threat to UK agriculture via the import of contaminated animals and animal products. Infection is rarely fatal, but it can have a dramatic impact upon the productivity of farm animals. The 2001 UK outbreak caused massive economic damage (billions of pounds) due to lost trade and impact upon farming communities. In addition, control of the disease through the slaughter of infected and high-risk animals was highly controversial and unpopular and led to heightened interest in a "vaccinate to-live policy". Vaccines are often of two types. The first are inactivated or 'killed' viruses which cannot infect the host but still prime the immune system to protect against later infection. The second are live viruses which are weakened or 'attenuated': they do infect the host thus triggering a superior immune response but are not strong enough to cause disease. Current vaccines for FMDV are only of the 'killed' type. In contrast, for the closely related human virus poliovirus, live 'attenuated' vaccines have been used to effectively control both disease and transmission such that global eradication of poliovirus is within sight. The effectiveness of current 'killed' vaccines for FMDV are limited by a number of factors and there is an urgent need to develop new control measures: we therefore wish to develop novel 'attenuated' vaccines, one of the goals of this research. To do this safely will require a detailed understanding of the complex interactions between FMDV and its host. Our proposed research will give novel insight into how FMDV interacts with its host-cell to achieve rapid replication or establish persistent infections. We will use this information to improve the effectiveness and safety of vaccines. The first strategy is to use modern molecular biology to change the virus, to make new strains that can protect animals without causing the debilitating disease - so-called live-attenuated viruses. The second strategy is to use the knowledge of how the virus grows in cells to make a new type of virus that could only grow in special 'helper' cells we will also create. Such viruses will not be able to grow in an animal and cause disease. This would make conventional 'killed' vaccine production a much safer process. Success in either approach would stimulate the routine use of vaccine to control FMDV around the globe. In the longer term, this could make a difference by reducing the overall, global incidence of FMD with enormous economic and social value worldwide. We argue that better control of FMD is essential for food security and must be coupled with the development of new vaccines, or new methods of producing vaccines, to make this policy effective. This is the purpose of our research.