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Basic Amino Acid Substitution at Residue 367 of the Envelope Protein of Tembusu Virus Plays a Critical Role in Pathogenesis

文献类型： 外文期刊

作者： Sun, Mengxu 1 ; Zhang, Lijiao 2 ; Cao, Yanxin 1 ; Wang, Jun 1 ; Yu, Ziding 1 ; Sun, Xue 1 ; Liu, Fengli 1 ; Li, Zhuolin 1 ;

作者机构： 1.China Agr Univ, Coll Vet Med, Key Lab Anim Epidemiol & Zoonosis, Minist Agr, Beijing, Peoples R China

2.Jiangsu Acad Agr Sci, Inst Vet Med, Nanjing, Peoples R China

3.Duke Univ, Sch Med, Dept Surg, Durham, NC 27708 USA

关键词： Tembusu virus; flavivirus; amino acid substitution; envelope protein; virulence; duck

期刊名称：JOURNAL OF VIROLOGY （ 影响因子：5.103； 五年影响因子：5.078 ）

ISSN： 0022-538X

年卷期： 2020 年 94 卷 8 期

页码：

收录情况： SCI

摘要： Tembusu virus (TMUV) is a flavivirus responsible for panzootic outbreaks of severe egg-drop and fatal encephalitis of domestic waterfowl in China. Although TMUV can be attenuated by in vitro passaging, experimental evidence supporting the role of specific genetic changes in virulence attenuation is currently lacking. Here, we performed site-directed mutagenesis on five envelope (E) protein amino acid residues in accordance with the attenuated TMUV generated in our recent study. Our results showed that the Thr-to-Lys mutation of residue 367 in E protein (E367) plays a predominant role in viral cell adaptation and virulence attenuation in ducks compared with mutations in other residues. We further demonstrated that the positively charged basic amino acid substitution at E367 enhanced the viral binding affinity for glycosaminoglycans (GAGs) and reduced viremia levels and the efficiency of replication in major target organs in subcutaneously inoculated ducks. Interestingly, the T367K mutation increased viral neutralization sensitivity to the early immune sera. Together, our findings provide the first evidence that a basic amino acid substitution at E367 strongly impacts the in vitro and in vivo infection of TMUV. IMPORTANCE Outbreaks of Tembusu virus (TMUV) infection have caused huge economic losses in the production of domestic waterfowl since the virus was first recognized in China in 2010. To control TMUV infection, a live-attenuated vaccine candidate of TMUV was developed in our previous study, but the mechanisms of virulence attenuation are not fully understood. Here, we found that the Thr-to-Lys substitution at E367 is a crucial determinant of TMUV virulence attenuation in ducks. We demonstrated that the T367K mutation attenuates TMUV through reducing viral replication in the blood, brain, heart (ducklings), and ovaries. These data provide new insights into understanding the pathogenesis of TMUV and the rational development of novel TMUV vaccines.

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