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

英国和巴西的家禽行业正在为最便宜和最容易获得的肉类蛋白质来源做出重大贡献。英国家禽业对国民经济的贡献约为40亿GB，而巴西是仅次于美国和中国的最大家禽和家禽产品生产国。尽管产量如此之高，传染病仍然是在全球范围内实现对禽类产品日益增长的需求的主要障碍。传染病造成的总损失是巨大的。例如，全球仅马立克氏病病毒(MDV)--一种家禽致癌病毒--造成了20亿GB的损失。大规模疫苗应用仍然是控制病毒的主要疾病控制工具。尽管广泛接种了针对病毒的疫苗(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，并突显出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。这些差距使我们对鸡参与人畜共患流感的分子机制负有责任，因此，作为唯一选择的受感染禽类的检疫和屠宰，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个基因(在人类中超过350个)的表达，称为干扰素刺激基因(ISGs)。利用这些ISGs有可能被应用于疫苗生产、更好的疫苗接种方案和控制感染。在这项建议中，我们将初步确定鸡ISGs的性质和数量，并研究其对临床表现从轻度到重度感染家禽(鸡、鸭、火鸡)的五种禽类病毒的效果。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重要性。使用广泛的图谱系统，我们将识别鸡细胞中那些抑制或增强病毒感染的chISGs。一旦确定，增强病毒感染的因素将在已建立的鸡细胞系中过度表达，而抑制病毒感染的因素将在鸡细胞中被移除或沉默。这种改良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很高，即使病毒产量增加十倍(这是有可能实现的)，也将对疫苗成本产生重大影响。除了与工业相关外，这项将由英国皮尔布赖特研究所和巴西坎皮纳斯州立大学联合实施的新提案，对于了解病毒诱导鸡的干扰素系统的机制至关重要，其中一些机制将适用于其他物种，如鸭子或火鸡。最后，该项目的结果将非常有价值地检验CHISG的能力，以保护鸡免受家禽重要病毒和那些可以从家禽转变为人类的病毒的影响。

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.