Bilateral BBSRC-FAPESP Research Grant: Dissecting Essential Roles of Chicken Interferon Stimulated Genes in the Pathobiology of Poultry Viruses

英国和巴西的家禽业为最便宜和最容易获得的肉类蛋白质来源做出了重大贡献。英国家禽业为国民经济贡献了约40亿英镑，而巴西是继美国和中国之后最大的家禽和家禽产品生产国。尽管产量很高，但传染病仍是全球实现对家禽产品日益增长需求的主要障碍。传染病造成的总损失是巨大的。例如，仅马立克氏病病毒（MDV），一种引起家禽癌症的病毒，就在全世界造成了20亿英镑的损失。大量接种疫苗仍然是防治病毒的主要手段。尽管广泛接种病毒疫苗（例如每年仅为MDV接种220亿剂疫苗），但家禽疾病的威胁正在上升，并突出表明我们对家禽对病毒自然感染的反应或免疫（疫苗）的基本理解存在差距。这些空白使我们在鸡参与流感人畜共患病的分子机制上负债累累，结果，作为唯一的选择，检疫和屠宰受感染的家禽，使家禽业损失了数十亿美元。病毒感染禽类细胞后产生的干扰素刺激数百种基因（人类超过350种）的表达，称为干扰素刺激基因（ISGs）。利用这些ISGs可能有助于疫苗生产、更好的疫苗接种方案和控制感染。在本提案中，我们将初步确定鸡ISGs （chISGs）的性质和大小，并研究它们对引起家禽（鸡、鸭、火鸡）感染的五种禽流感病毒的作用，这些病毒的临床表现从轻微到严重不等。这些病毒不仅对英国和巴西，而且对全世界都具有巨大的商业和人畜共患病重要性。使用广泛的分析系统，我们将识别鸡细胞中抑制或增强病毒感染的chisg。一旦确定，增强病毒感染的因子将在已建立的鸡细胞系中过度表达，而抑制病毒感染的因子将在鸡细胞中被去除或沉默。这种经过修饰的细胞系将用于增加病毒的复制，用于工业疫苗生产和实验室规模的病毒分离。鉴于目前全球家禽疫苗市场规模很大，即使病毒产量增加10倍（这是可能实现的），也会对疫苗成本产生重大影响。除了工业意义之外，这项由英国皮尔布赖特研究所和巴西坎皮纳斯州立大学联合开展的新提案，对于理解病毒诱导鸡的干扰素系统的机制至关重要，其中一些将适用于其他物种，如鸭或火鸡。最后，该项目的研究结果对于检验chigs保护鸡免受家禽重要病毒和那些可以从家禽转移到人类的病毒的能力将非常有价值。

Poultry sectors of the UK and Brazil are contributing significantly to the cheapest and the most accessible source of meat protein. The UK poultry industry is contributing around £4 billion to the national economy whereas Brazil is the largest producer of poultry and poultry products, after United States and China. Despite this high production, infectious diseases are a major hurdle in achieving increasing demands of poultry products, around the globe. The total losses caused by infectious disease are enormous. For example, only Marek's disease virus (MDV), a cancer-causing virus of poultry, accounts for £2 billion losses worldwide. Massive vaccines application remained major disease-controlling tool against viruses. Despite widespread vaccinations against viruses (e.g. 22 billion vaccine doses for MDV only per year), the threat from poultry diseases is on rise and highlights the gaps in our fundamental understanding of poultry responses against virus natural infections or in immunization (vaccines). Such gaps has left us indebted on the molecular mechanism of chicken's involvement in influenza zoonoses and as a result quarantine and slaughtering of infected birds, as only choice, cost the poultry industry billions of dollars. Interferons, produced following viral infection of avian cells, stimulate the expression of hundreds of genes (more than 350 in humans) called interferon stimulated genes (ISGs). Exploitation of these ISGs could potentially be applied in favour of vaccine production, better vaccination protocols and controlling infections. In this proposal, we will initially identify the nature and magnitude of chicken ISGs (chISGs) and study their effects against five avian viruses causing infections in poultry (chicken, duck, turkey) ranging from mild to severe in terms of clinical manifestation. These viruses are of immense commercial and zoonotic importance not only for UK and Brazil but also throughout the world. Using broad-range profiling systems, we will identify those chISGs in the chicken cells that inhibit or enhance virus infections. Once identified, the factors that enhance virus infection will be overexpressed in established chicken cell line and the ones that inhibit virus infection will be removed or silenced within chicken cells. This modified cell line will be used to increase the replication of viruses for both industrial vaccine production and laboratory scale virus isolation. Given the fact that the current global poultry vaccine market is high, even a ten-fold increase in virus yield, which is potentially achievable, would have significant impact on the cost for vaccine. Beside industrial relevance, this new proposal, to be carried out jointly between The Pirbright Institute, UK and the State University of Campinas, Brazil, is crucial to understand the mechanism by which viruses induce interferon system of the chicken, some of which will be applicable to other species such as duck or turkeys. Finally, the findings from the project will be very valuable in examining the ability of the chISGs to protect the chickens against viruses of both poultry importance and those that can switch from poultry to human.