Molecular determinants of cellular resistance to Newcastle disease virus infection

新城疫(ND)是世界上最严重的禽类疾病之一，新城疫疫情对加拿大家禽业构成了无时无刻不的威胁：这是一项价值数十亿美元的业务，极大地促进了加拿大经济的发展。新城疫是由新城疫病毒(NDV)株引起的，新城疫病毒是副粘病毒科新城疫病毒属的成员。新城疫的控制是通过大规模疫苗接种计划在世界范围内进行的。尽管如此，50多年来广泛的疫苗接种未能阻止该病毒在全球范围内的传播和演变。事实上，尽管疫苗在以最佳方式使用时能够防止临床症状，但不能提供无菌免疫，也不能阻止挑战病毒的复制和脱落。由于缺乏无菌免疫力和高新城疫病毒变异率，新城疫在许多国家被证明几乎不可能根除。拟议的目标侧重于在细胞水平上发现和表征新城疫病毒感染的抵抗力决定因素。新城疫病毒细胞抗性宿主基因的发现和鉴定最终可以为亲本家禽的选育提供更合理的策略。这项拟议的研究在调查抵抗新城疫病毒感染的基本机制的同时，有可能提高我们在全球范围内控制新城疫的能力。

Newcastle disease (ND) is one of the most severe avian diseases worldwide, and ND outbreaks represent an ever-present threat to the Canadian poultry industry: a multibillion dollar business that significantly adds to the Canadian economy. ND is caused by strains of Newcastle disease virus (NDV), a member of the Avulavirus genus, Paramyxoviridae family. Control of ND is carried out worldwide through large-scale vaccination programs. Nonetheless, over 50 years of extensive vaccination has failed to prevent the spread and evolution of the virus worldwide. In fact, although able to prevent clinical signs when optimally administered, vaccines do not confer sterile immunity, and cannot prevent replication and shedding of the challenge virus. Because of lack of sterile immunity and the high NDV mutation rates, ND has proven all but impossible to eradicate in many countries. If animals that have a reduced rate of infection against NDV are utilized, it may be possible to considerably decrease the rate of viral spread, evolution and to decrease the cost of controlling ND.***The long-term goal of this new research program is to discover and characterize determinants of resistance to Newcastle disease virus infection at a cellular level, which could ultimately lead to generation of NDVresistant birds through novel cloning or selective breeding strategies.***Pursuant to this overarching goal, my short-term objectives are:***1. To identify components of the NDV ribonucleoprotein (RNP) complex that can induce resistance to NDV infection through the superinfection exclusion (SE) phenomenon.***2. To identify intrabodies against NDV RNP that can inhibit NDV replication.***3. To discover cellular genes that are essential for NDV infection and replication, using a genome walking strategy in a haploid cell line.***Significance. The proposed Objectives focus on discovery and characterization of determinants of resistance to NDV infection at a cellular level. Characterization of the superinfection exclusion phenomenon, and discovery of NDV-specific intrabodies commits to an over-riding goal to characterize a platform for production of transgenic birds that are resistant not only to NDV, but also to other infectious agents of poultry. Discovery and characterization of host genes responsible for cellular resistance to NDV can eventually lead to more rational selective breeding strategies of parent poultry stocks. The proposed research, while investigating basic mechanisms of resistance to NDV infection, has the potential to improve our ability to control ND on a global scale.**