寨卡病毒的-1结构对于感染期间的sfRNA存在和细胞病变效应至关重要
Monica E Graham1, Camille Merrick2, Benjamin M Akiyama3
1Department of Immunology and Microbiology, University of Colorado School of Medicine , Aurora, Colorado, USA.
mBio
|July 7, 2023
概括
寨卡病毒-1RNA结构的突变通过降低非编码sfRNA水平来削弱病毒,影响细胞死亡,免疫逃避和病原性. 这表明,准这些RNA结构可能有助于疫苗开发.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 结构RNA结构RNA结构
背景情况:
- 弗拉维病毒,包括寨卡病毒 (ZIKV),在其3'未翻译区域 (3' UTR) 具有保存的RNA结构,对于病毒复制,翻译和病原性至关重要.
- 在ZIKV 3' UTR中,-1 (DB-1) 结构对于正链基因组复制至关重要,但其确切的功能作用和对病原发生的贡献尚不清楚.
研究的目的:
- 调查ZIKV DB-1 RNA结构在病毒病变发生过程中的功能意义.
- 阐明DB-1结构影响病毒复制,免疫逃避和疾病结果的机制.
主要方法:
- 设计并生成了两种ZIKV传染性克隆 (ZIKV-TL.PK和ZIKV-p.2.5') 具有破坏DB-1三级结构的突变.
- 评估了病毒阳性链基因组复制,细胞病变效应,caspase-3激活,sfRNA水平,sfRNA生物发生和对I型干扰素的敏感性.
- 利用干扰素I/II型受体淘汰小鼠来评估病毒病原和在大脑组织中的复制.
主要成果:
- 寨卡病毒DB-1突变病毒与野生型 (WT) 寨卡病毒类似地复制,但表现出明显减少的细胞病变效应和caspase-3激活.
- 在感染期间,DB-1突变者显示sfRNA水平降低,尽管sfRNA生物发生在体外未发生变化.
- 突变病毒对I型干扰素有增强的敏感性,并在淘汰赛小鼠的大脑组织中减弱复制,从而降低了发病率和死亡率.
结论:
- 弗拉维病毒DB-1RNA结构对于在感染期间维持sfRNA水平至关重要,这反过来又支持酶-3依赖的细胞病变效应,I型干扰素耐药性和整体病毒病原性.
- 针对DB-1RNA结构的有针对性的破坏减弱了ZIKV,这表明它作为开发新型疫苗候选人的战略潜力.
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