Comparative genomic analyses of a virulent pseudorabies virus and a series of its in vitro passaged strains
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Comparative genomic analyses of a virulent pseudorabies virus and a series of its in vitro passaged strains Chao Ye1†, Jiqiang Wu1†, Wu Tong1,2, Tongling Shan1,2, Xuefei Cheng1, Jingjing Xu1, Chao Liang1, Hao Zheng1,2, Guoxin Li1,2* and Guangzhi Tong1,2*
Abstract Background: Pseudorabies virus (PRV) of the family Herpesviridae is the causative agent of Aujeszky’s disease. Attenuation of PRV by serial passaging in vitro is a well-established method; however, the dynamic variations occurring on viral genome during this process have not been characterized. Methods: Genome sequencing and comparative genomic analyses of a virulent pseudorabies virus and a series of its plaque-purified strains via serial passaging in vitro were performed, and the properties in vitro and in vivo of which were further characterized. Results: Compared to the parental virus, replication in vitro was enhanced in the highly passaged F50, F91, and F120. In contrast, lethality in mice decreased gradually with passage number. Genome sequencing of F50, F91, and F120 showed deletion of a large fragment containing gE, which is likely related to their attenuation. In addition, single nucleotide variations were identified in many genes of F50, F91, and F120. In-frame and frameshift indels were also detected in specific genes of passaged strains. Particularly frameshift mutations were observed in highly passaged strains, resulting in a truncated but overexpressed pUL46. Conclusion: During attenuation of PRV by serial passaging in Vero cells, dynamic variation patterns including a large deletion, single nucleotide variations, small in-frame indels, and also frameshifts mutations successively emerged, contributing to evolution of the viral population and enabling the gradual attenuation of the virus. These data provide clues to better understand PRV attenuation during passaging. Keywords: Pseudorabies virus, Genomic analyses, Passaging, Attenuation, Dynamic variation
Introduction Pseudorabies virus (PRV) of the family Herpesviridae, subfamily Alphaherpesvirinae [1], is the causative agent of Aujeszky’s disease, a major viral disease in pigs, the virus natural reservoir. It causes severe neurological disease and high mortality in newborn piglets, and reproductive failure in sows [2], resulting in significant economic losses to the pig industry worldwide. Besides pigs, PRV can infect numerous mammals causing neurological disease and acute death [3]. * Correspondence: [email protected]; [email protected]; [email protected] † Chao Ye and Jiqiang Wu contributed equally to this work. 1 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, No. 518, Ziyue Road, Minhang District, Shanghai 200241, China Full list of author information is available at the end of the article
Effective vaccines have long been available for PRV [4]. Among the various vaccines used, the attenuated Bartha vaccine strain, a derivative of a virulent strain generated by extensive passage, has been the most commonly used [5]. Thus
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