RVFV毒性因子NSs触发了线粒体的MCL-1-BAK轴,以激活致病性NLRP3热
Zhenqiong Guan1,2, Huiling Li1,2, Chongtao Zhang1
1State Key Laboratory of Virology, Center for Antiviral Research, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China.
裂谷热病毒 (RVFV) 非结构蛋白NSs触发线粒体损伤和NLRP3炎症酶激活,导致严重的炎症和致命的疾病. 这种机制涉及宿主转录抑制,导致细胞死亡和病毒病原性.
科学领域:
- 病毒学 病毒学
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
背景情况:
- 裂谷热病毒 (RVFV) 感染会引起严重的炎症,但激活机制尚不清楚.
- RVFV是一种高度致病的,由蚊子传播的动物性病毒.
- 炎症酶,特别是NLRP3,是炎症的关键调节者.
研究的目的:
- 阐明RVFV引发炎症和病变的机制.
- 研究RVFV非结构性蛋白NSs在炎症酶激活中的作用.
- 确定NLRP3炎症酶对RVFV引起的致命感染的贡献.
主要方法:
- 研究了RVFV NSs蛋白对宿主转录和线粒体通路的影响.
- 利用了骨髓细胞白血病-1 (MCL-1) 和Bcl-2蛋白家族的相互作用.
- 采用了NSs突变病毒 (RVFV-NSsRM) 和NLRP3淘汰赛小鼠模型.
- 评估了线粒体活性氧物种 (mtROS) 和氧化线粒体DNA (ox-mtDNA) 的释放.
- 分析了NLRP3-GSDMD热和炎症病原.
主要成果:
- RVFV NSs 蛋白质抑制宿主转录,降低调节MCL-1.
- 降低MCL-1的调节激活BAK,导致mtROS和ox-mtDNA的释放.
- 细胞质的ox-mtDNA激活了NLRP3炎症体,导致NLRP3-GSDMD烧灭.
- RVFV-NSsRM突变并没有诱导MCL-1下调或灭.
- Nlrp3-/-小鼠在RVFV感染时显示炎症病原和死亡率降低.
结论:
- RVFV NSs蛋白通过MCL-1-BAK轴触发线粒体损伤,激活NLRP3炎症酶.
- 依赖NLRP3的热是RVFV炎症病原和致死性的关键机制.
- 针对NSs诱导的线粒体通路提供了针对RVFV的潜在治疗策略.
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