流感病毒感染重新编程胆固醇生物合成,以促进病毒通过TAK1-RORγ轴的复制
Jingting Zhang1, Ruixuan Cao1, Yujie Wang1
1College of Veterinary Medicine, Institute of Comparative Medicine, Yangzhou University, Yangzhou, China.
PLoS pathogens
|October 24, 2025
概括
流感A病毒感染通过激活与视网膜酸相关的孤儿受体γ (RORγ) 来促进细胞胆固醇的产生. 抑制RORγ减少病毒复制,提供了一个潜在的治疗标.
科学领域:
- 病毒学 病毒学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 包裹病毒,包括流感A病毒 (IAV),依赖宿主细胞胆固醇进行复制.
- IAV操纵宿主胆固醇生物合成的机制尚未完全理解.
研究的目的:
- 阐明IAV感染调节宿主胆固醇生物合成的分子机制.
- 研究与视网膜酸相关的孤儿受体γ (RORγ) 在IAV诱导的胆固醇产生和病毒复制中的作用.
主要方法:
- 研究了IAV诱导的RORγ表达及其与SREBP2.2的相互作用.
- 使用了RORγ淘汰模式和药理抑制剂 (XY018,GSK805).
- 评估了HMGCR表达,胆固醇生物合成,病毒复制和炎症标志物在体外和体内.
主要成果:
- IAV感染上调RORγ表达,该表达与SREBP2合作,增强HMGCR表达和胆固醇生物合成.
- 抑制或淘汰RORγ抑制了IAV诱导的胆固醇产生和病毒复制.
- 外源胆固醇拯救了RORγ抑制的抗病毒作用.
- IAV通过TAK1/JNK/IKK通路激活RORγ,从而导致AP1和NF-κB的激活.
- 在体内,RORγ缺乏或抑制降低了病毒载量,缓解症状,并改善了感染IAV的小鼠的生存率.
结论:
- IAV感染劫持RORγ-SREBP2-HMGCR轴以增加细胞胆固醇,促进病毒复制.
- 向RORγ代表了对抗流感A病毒的有希望的治疗策略.
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