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

点击翻译按钮获取中文摘要

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.