Studies on Molecular Mechanisms of Host-Pathogen Interactions of Nidoviruses of Veterinary Importance

猪繁殖和呼吸综合征病毒(PRRSV)和猪流行性腹泻病毒(PEDV)造成严重的农业经济损失，被认为是加拿大和世界范围内的主要新兴牲畜病原体。这两种病毒都是单链、正义RNA、被包裹的猪*Nido病毒，并有共同的特征，包括相似的颗粒*结构、保守的基因组组织和复制策略。传统的疫苗开发方法并没有产生可靠和有效的疫苗，这些病毒仍然是全球养猪业的主要威胁。*我们认为，对NidVirus-宿主相互作用的了解不足阻碍了NidoVirus有效疫苗的开发。因此，我们建议研究动物NidoVirus-宿主相互作用的分子机制，以确定新的抗病毒靶点并*开发有效的预防策略。*该计划的长期目标是更好地了解动物NidoVirus与其宿主之间相互作用的分子*机制，以便*开发有效控制病毒感染的新策略。未来五年的短期目标是通过重点研究NidVirus感染的早期事件的特征和比较，阐明PRRSV和PEDV与宿主细胞的相互作用。为了实现这一目标，我们将：1)研究猪NIDV进入宿主细胞的细胞和分子机制，2)分析宿主细胞对病毒*感染反应的蛋白质组谱，表征NidoVirus的组成，并鉴定与病毒颗粒相关的宿主*蛋白质。这些具体目标的实现将使我们了解在NidVirus感染的最早阶段*病毒与宿主相互作用的性质。我们将确定与病毒基因组和蛋白质相互作用的细胞因子，以及整合到病毒颗粒中并参与病毒感染调控的宿主蛋白质。我们将绘制高度保守和强大的病毒蛋白抗原表位图，这些表位在病毒进入过程中瞬间暴露，是疫苗设计的重要靶点。这些结果将为我们的研究计划提供工具和方向，调查病毒基因组和蛋白质在宿主细胞内的细胞内运输，病毒组装和释放的机制，以及NidoVirus为促进感染和逃避宿主监视而利用和重排的细胞途径。更重要的是，我们的发现将为抗病毒疫苗的开发提供新的具体目标。我们的发现也将与许多其他被包膜的动物病毒相关。*

The porcine reproductive and*respiratory syndrome virus (PRRSV) and the porcine epidemic diarrhea virus*(PEDV) are responsible for severe agricultural economic losses and are*considered to be the primary emerging livestock pathogens in Canada and worldwide.*Both viruses are single-stranded, positive-sense RNA, enveloped porcine*nidoviruses and share common characteristics including similar particle*structure, conserved genomic organization and replication strategy. The*traditional approach to develop vaccines has not resulted in reliable and*effective vaccines, and these viruses remain a major threat to the swine*industry worldwide.***We believe that insufficient*understanding of nidovirus-host interactions hinders the development of*effective vaccines against nidoviruses. Therefore, we propose to investigate the molecular mechanisms of animal*nidovirus-host interactions in order to identify novel antiviral targets and*develop effective prevention strategies.***The*long-term goal of this program is to gain a better understanding of the molecular*mechanisms of interactions between animal nidoviruses and their hosts in order*to develop new strategies for effective control of viral infections. The short-term*goal for the next five years is to elucidate PRRSV and PEDV interactions with*host cells by focusing on the characterization and comparison of early events*in nidovirus infection. To address this objective, we will: 1) investigate the*cellular and molecular mechanisms underlying porcine nidovirus entry into host*cells, and 2) analyze proteomic profiles of host cell responses to viral*infection, characterize the composition of nidoviruses, and identify the host*proteins associated with the viral particle. The accomplishment of these*specific objectives will lead to an understanding of the nature of the*virus-host interaction during the earliest stage of nidovirus infection. We*will identify cellular factors interacting with the viral genome and proteins,*as well as host proteins that are incorporated into viral particles and*involved in modulation of viral infection. We will map the highly conserved and*potent antigenic epitopes of viral proteins, which are transiently exposed*during the process of virus entry and represent important targets for vaccine*design. These results will provide tools and directions for the continuation of*our research program in the investigation of intracellular trafficking of the viral*genome and proteins within the host cell, the mechanisms of viral assembly and*release, and the cellular pathways exploited and rearranged by nidoviruses to*facilitate infection and evade host surveillance. More importantly, our*findings will provide new specific targets for antiviral vaccine development. Our*findings will also be relevant to many other enveloped animal viruses. *** ***