经典猪瘟病毒非结构性蛋白4A招募二酸酸脱酶以促进病毒复制
Bing-Qian Zhao1, Jing Chen1, Jin-Xia Chen1
1MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
Journal of virology
|May 17, 2024
概括
双酸脱酶 (DHODH) 抑制剂通过阻断皮里米丁合成和增强先天免疫力,对古典猪瘟病毒 (CSFV) 具有强大的抗病毒活性. CSFV非结构蛋白4A (NS4A) 与DHODH相互作用,促进病毒复制.
科学领域:
- 病毒学 病毒学
- 生物化学 生物化学
- 免疫学 免疫学 免疫学
背景情况:
- 线粒体在细胞能量生产和先天性免疫反应中起着至关重要的作用,影响病毒复制.
- 经典猪瘟病毒 (CSFV) 在全球猪群中造成重大经济损失.
- 在此之前,dihydroorotate dehydrogenase (DHODH) 在杀虫病毒复制中的作用是未知的.
研究的目的:
- 确定针对线粒体的新型抗病毒化合物,以对抗CSFV.
- 研究DHODH抑制剂影响CSFV复制的机制.
- 阐明CSFV非结构蛋白4A (NS4A) 和DHODH之间的相互作用.
主要方法:
- 对382种针对线粒体的化合物的查.
- 通过EC50测定和病毒RNA合成抑制来评估抗病毒活性.
- 研究先天性免疫路径 (TBK1-IRF3-STAT1,NF-κB) 和金胺合成.
- 使用DHODH敲除,共聚焦显微镜和免疫沉试验.
主要成果:
- DHODH 抑制剂对CSFV表现出强大的抗病毒活性 (EC50:0.97526.635 nM).
- 抑制剂通过增强先天免疫力和抑制de novo胺合成来阻止病毒RNA合成.
- CSFV NS4A 蛋白与 DHODH 相互作用,增强其活性并促进病毒复制.
- DHODH对于CSFV复制至关重要,特定的氨基酸区域调解NS4A-DHODH相互作用.
结论:
- DHODH是CSFV复制的关键宿主因素.
- DHODH 抑制剂代表了对CSFV的一种有前途的治疗策略.
- 在调节宿主DHODH活动以促进病毒传播方面,CSFV NS4A具有新的功能.
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