Molecular determinants of cellular resistance to Newcastle disease virus infection

新城疫病（ND）是世界上最严重的禽类疾病之一，ND的爆发对加拿大家禽业构成了永远存在的威胁：这是一个数十亿美元的行业，大大增加了加拿大的经济。新城疫是由新城疫病毒（NDV）毒株引起的，NDV是副粘病毒科阿武拉病毒属的一员。ND的控制是通过大规模疫苗接种规划在世界范围内进行的。尽管如此，50多年来的广泛疫苗接种未能阻止病毒在世界范围内的传播和演变。事实上，疫苗虽然能够在适当的情况下预防临床症状，但不能提供无菌免疫，也不能防止挑战病毒的复制和脱落。由于缺乏无菌免疫和NDV高突变率，ND在许多国家已被证明几乎不可能根除。如果使用对新城疫感染率较低的动物，就有可能大大降低病毒传播和进化的速度，并降低控制新城疫的成本。

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 NDV-resistant 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.