Molecular determinants of cellular resistance to Newcastle disease virus infection

细胞抵抗新城疫病毒感染的分子决定因素

• 批准号: RGPIN-2016-03802
• 负责人: Susta, Leonardo
• 金额: $ 2.26万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761931
• 关键词: Molecular; determinants; cellular; resistance; Newcastle

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.

新城疫 (ND) 是全球最严重的禽类疾病之一，新城疫的爆发对加拿大家禽业构成了始终存在的威胁：这一价值数十亿美元的业务极大地促进了加拿大经济的发展。 ND 是由新城疫病毒 (NDV) 菌株引起，NDV 是副粘病毒科禽病毒属的成员。新城疫的控制在世界范围内通过大规模疫苗接种计划进行。尽管如此，50多年来的广泛疫苗接种未能阻止病毒在全球范围内的传播和进化。事实上，虽然在最佳施用时能够预防临床症状，但疫苗不能赋予无菌免疫力，并且不能阻止攻击病毒的复制和脱落。由于缺乏无菌免疫力和新城疫病毒突变率高，新城疫在许多国家已被证明几乎不可能根除。如果使用新城疫病毒感染率较低的动物，就有可能大大降低病毒传播和进化的速度，并降低控制新城疫病毒的成本。这项新研究计划的长期目标是在细胞水平上发现和表征新城疫病毒感染抗性的决定因素，这最终可能通过新的克隆或选择性育种策略产生抗新城疫病毒的鸟类。 为了这个总体目标，我的短期目标是： 1．鉴定新城疫病毒核糖核蛋白（RNP）复合物的成分，通过重复感染排除（SE）现象诱导对新城疫病毒感染的抵抗力。 2．鉴定可抑制NDV复制的NDV RNP胞内抗体。3．在单倍体细胞系中使用基因组行走策略来发现新城疫病毒感染和复制所必需的细胞基因。意义。拟议的目标侧重于在细胞水平上发现和表征抗新城疫病毒感染的决定因素。双重感染排除现象的表征以及NDV特异性胞内抗体的发现致力于构建一个用于生产转基因禽类的平台的首要目标，这些转基因禽类不仅对NDV具有抗性，而且对家禽的其他传染性病原体也具有抗性。负责细胞抗新城疫病毒的宿主基因的发现和表征最终可以导致亲本家禽种群的更合理的选择性育种策略。拟议的研究在调查新城疫病毒感染的基本抵抗机制的同时，有可能提高我们在全球范围内控制新城疫的能力。