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

我们面临的最大挑战之一将是满足日益增长的粮食需求，特别是在发展中国家以及印度和中国等对肉类产品需求不断增长的经济体。动物疾病对畜牧业的生产力有重大影响，保障动物福利将是最大限度地提高粮食产量的一个重要组成部分。口蹄疫病毒（Foot-and-mouth disease virus，FMDV）是一种感染家畜（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，也是最令人恐惧的病毒，因为这种病毒可以非常迅速地传播。该病毒还可以引起长期的“持续性”感染，这些感染很难在现场诊断，并使疾病控制复杂化。FMDV还可以感染许多野生动物物种，并且在非洲，野生动物中的持续感染提供了可能感染家畜的重要宿主。FMDV在地球仪引起疾病，并且通过受污染的动物和动物产品的进口对英国农业构成持续威胁。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年英国爆发的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，通过屠宰受感染和高风险动物来控制这一疾病，引起了很大争议，也不受欢迎，导致人们对“接种疫苗以维持生命政策”的兴趣增加。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，但仍能激发免疫系统以防止以后的感染。第二种是弱化或“减毒”的活病毒：它们确实感染宿主，从而引发上级免疫反应，但不足以引起疾病。目前FMDV疫苗仅为“灭活”型。相比之下，对于密切相关的人类病毒脊髓灰质炎病毒，活的“减毒”疫苗已被用于有效地控制疾病和传播，使得全球根除脊髓灰质炎病毒指日可待。目前的FMDV“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。为了安全地做到这一点，需要详细了解FMDV与其宿主之间的复杂相互作用。我们提出的研究将为FMDV如何与宿主细胞相互作用以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，制造出可以保护动物而不会导致衰弱疾病的新毒株--所谓的减毒活病毒。第二个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“辅助”细胞中生长。这种病毒将不能在动物体内生长并引起疾病。这将使传统的“灭活”疫苗生产成为一个更安全的过程。任何一种方法的成功都将刺激疫苗的常规使用，以控制地球仪各地的FMDV。从长远来看，这可能会通过减少全球口蹄疫的总体发病率而产生影响，在全球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是必不可少的，必须与新疫苗的开发或生产疫苗的新方法相结合，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.