Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Vaccine Institute, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Immunology, University of Washington, Seattle, WA 98195-76504, USA.
Virology. 2010 Mar 30;399(1):1-10. doi: 10.1016/j.virol.2009.12.031. Epub 2010 Jan 25.
Alphaviruses are mosquito-borne viruses that cause serious human and animal diseases. Previous studies demonstrated that a determinant within the nsP1/nsP2 cleavage domain of the virulent Sindbis AR86 virus played a key role in regulating adult mouse virulence without adversely affecting viral replication. Additional characterization of this determinant demonstrated that a virus with the attenuating mutation induced more type I IFN production both in vivo and in vitro. Interestingly, this phenotype was not specific to the Sindbis AR86 virus, as a similar mutation in a distantly related alphavirus, Ross River Virus (RRV), also led to enhanced IFN induction. This effect was independent of virus-induced host shutoff, since IRF-3 phosphorylation, which occurs independently of de novo host transcription/translation, was induced more robustly in cells infected with the mutant viruses. Altogether, these results demonstrate that critical determinants within the nsP1/nsP2 cleavage domain play an important role in regulating alphavirus-induced IFN responses.
甲病毒是通过蚊子传播的病毒，可引起人类和动物的严重疾病。先前的研究表明，在强毒西尼罗河病毒（Sindbis AR86 病毒）的 nsP1/nsP2 切割域内的一个决定因素在调节成鼠毒力方面发挥了关键作用，而不会对病毒复制产生不利影响。对该决定因素的进一步表征表明，具有减弱突变的病毒在体内和体外均可诱导更多的 I 型 IFN 产生。有趣的是，这种表型并非西尼罗河病毒所特有，因为在亲缘关系较远的甲病毒罗斯河病毒（RRV）中存在类似的突变，也导致 IFN 诱导增强。这种效应不依赖于病毒诱导的宿主关闭，因为发生在不依赖于从头转录/翻译的 IRF-3 磷酸化在感染突变病毒的细胞中更强烈地诱导。总的来说，这些结果表明 nsP1/nsP2 切割域内的关键决定因素在调节甲病毒诱导的 IFN 反应中起着重要作用。
