结核菌抑制宿主抗菌通过脱L-氨酸抑制宿主抗菌
Cheng Peng1,2, Yuanna Cheng1,2, Mingtong Ma1,2
1Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
Nature communications
|May 17, 2024
概括
结核菌抑制宿主免疫力通过水解L-氨酸,防止抗微生物 (AMP) 诱导. 恢复L-氨酸或抑制氨酸脱酶 (Ald) Rv2780可增强AMP并对抗M.结核病感染.
科学领域:
- 免疫学 免疫学 免疫学
- 微生物学 微生物学
- 生物化学 生物化学
背景情况:
- 抗微生物 (AMP) 对于宿主防御至关重要,但在Mycobacterium tuberculosis (M. tuberculosis) 感染期间诱导不良.
- 结核菌在巨细胞中逃避AMP诱导的机制尚不清楚.
研究的目的:
- 为了阐明M.结核病介导的AMP诱导抑制的机制.
- 为了确定M.结核病感染的潜在治疗点.
主要方法:
- 研究了L-alanine,PRSS1和NF-κB通路之间的相互作用.
- 从M.结核病中利用氨酸脱酶 (Ald) Rv2780来化L-氨酸.
- 使用小鼠模型评估了L-alanine和Rv2780抑制对AMP表达和M.结核病毒性 in vivo的影响.
- 评估了L-alanine和Rv2780抑制剂GWP-042对M.结核病感染的疗效.
主要成果:
- 与PRSS1的L-氨酸相互作用激活NF-κB通路,诱导AMP的表达.
- 结核菌 Ald Rv2780 化L-氨酸,抑制AMP并促进细菌的生存.
- 通常,PRSS1通过破坏TAK1/TAB1复合体来抑制NF-κB;与PRSS1结合的L-氨酸可以逆转这种抑制.
- 删除抗微生物基因Defb4损害了Rv2780的毒性.
- 在体内,L-氨酸和Rv2780抑制剂GWP-042对M.结核病感染表现出显著的抑制活性.
结论:
- 结核病菌使用其氨酸脱酶 (Ald) Rv2780来抑制宿主AMP的产生,这是一种新的免疫逃避策略.
- 向Rv2780或调节L-alanine水平为M.结核病感染提供了一个有希望的治疗方法.
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