MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis.
MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis.
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MERS-COV辅助ORF在感染和发病机理中起关键作用。
DOI：
10.1128/mbio.00665-17
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发表时间：
2017-08-22
期刊：
影响因子：
6.4
通讯作者：
Baric RS
中科院分区：
文献类型：
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作者：
Menachery VD;Mitchell HD;Cockrell AS;Gralinski LE;Yount BL Jr;Graham RL;McAnarney ET;Douglas MG;Scobey T;Beall A;Dinnon K 3rd;Kocher JF;Hale AE;Stratton KG;Waters KM;Baric RS
虽然冠状病毒 (CoV) 附属开放阅读框 (ORF) 蛋白对于病毒复制来说是可有可无的，但它通常在感染和发病机制中发挥关键作用。利用先前生成的突变体，我们证明所有四种中东呼吸综合征冠状病毒 (MERS-CoV) 附属 ORF 的缺失（ORF3、-4a、-4b 和 -5 [dORF3-5] 的删除）对病毒复制和发病机制具有重大影响。重要的是，dORF3-5 突变体的减弱主要是由宿主反应失调驱动的，包括细胞过程破坏、干扰素 (IFN) 途径激活增强和强烈的炎症。体外复制减毒也扩展到体内模型，允许使用 dORF3-5 作为活减毒疫苗平台。最后，ORF5 的检查表明其在调节 NF-κB 介导的炎症中发挥部分作用。总之，这些结果证明了 MERS-CoV 辅助 ORF 对于发病机制的重要性，并强调它们作为未来监测和治疗的潜在目标。中东呼吸综合征冠状病毒的最初出现和周期性爆发凸显了人畜共患病原体对全球公共卫生构成的持续威胁。在这些研究中，突变病毒的产生证明了辅助 ORF 在 MERS-CoV 感染和发病机制中的必要性。考虑到这一点，辅助 ORF 功能可以针对 MERS-CoV 和相关 2C 组冠状病毒的治疗和疫苗治疗。此外，同时破坏辅助 ORF 可能会为基于 SARS 和 MERS-CoV 辅助 ORF 突变体的未来新出现菌株的减毒提供快速反应平台。
While dispensable for viral replication, coronavirus (CoV) accessory open reading frame (ORF) proteins often play critical roles during infection and pathogenesis. Utilizing a previously generated mutant, we demonstrate that the absence of all four Middle East respiratory syndrome CoV (MERS-CoV) accessory ORFs (deletion of ORF3, -4a, -4b, and -5 [dORF3-5]) has major implications for viral replication and pathogenesis. Importantly, attenuation of the dORF3-5 mutant is primarily driven by dysregulated host responses, including disrupted cell processes, augmented interferon (IFN) pathway activation, and robust inflammation. In vitro replication attenuation also extends to in vivo models, allowing use of dORF3-5 as a live attenuated vaccine platform. Finally, examination of ORF5 implicates a partial role in modulation of NF-κB-mediated inflammation. Together, the results demonstrate the importance of MERS-CoV accessory ORFs for pathogenesis and highlight them as potential targets for surveillance and therapeutic treatments moving forward. The initial emergence and periodic outbreaks of MERS-CoV highlight a continuing threat posed by zoonotic pathogens to global public health. In these studies, mutant virus generation demonstrates the necessity of accessory ORFs in regard to MERS-CoV infection and pathogenesis. With this in mind, accessory ORF functions can be targeted for both therapeutic and vaccine treatments in response to MERS-CoV and related group 2C coronaviruses. In addition, disruption of accessory ORFs in parallel may offer a rapid response platform to attenuation of future emergent strains based on both SARS- and MERS-CoV accessory ORF mutants.