循环二-AMP抑制了Listeria monocytogenes在感染期间的无甲状腺死亡
Joshua P Leeming1, Omar M Elkassih1, Damilola T Oyebode1
1Department of Biology, University of Texas at Arlington, Arlington, TX, 76019, USA.
bioRxiv : the preprint server for biology
|June 4, 2025
概括
升高的循环二-AMP (c-di-AMP) 防止了Listeria monocytogenes的无甲状腺死亡 (TLD). 降低c-di-AMP水平可以提高抗生素在感染期间对耐药细菌的有效性.
科学领域:
- 微生物学 微生物学
- 细菌病原体的产生
- 分子生物学分子生物学
背景情况:
- 抗叶酸抗生素向Listeria monocytogenes (Lm) 中的甲基甲基甲酸合成酶 (ThyA),诱导无甲基甲酸死亡 (TLD).
- 在感染期间TLD的确切机制仍然不完全理解.
- 细菌的第二信使循环二-AMP (c-di-AMP) 通过抗叶酸治疗进行上调.
研究的目的:
- 阐明c-di-AMP在感染期间Lm中调节TLD中的作用.
- 研究c-di-AMP调节对Lm生长和毒性的影响.
- 为了确定参与c-di-AMP介导的TLD的宿主-病原体相互作用.
主要方法:
- Lm突变的生成和表征 (例如,ΔthyA).
- 在体外检测细菌生长,细胞死亡和胆胺饥饿.
- 在体内小鼠感染模型 (口服和静脉注射) 评估细菌负担和毒性.
- 分析c-di-AMP水平和c-di-AMP结合蛋白PstA的作用.
主要成果:
- 升高的c-di-AMP对于抑制Lm中的TLD至关重要.
- 在ΔthyA突变体中c-di-AMP的耗尽增加了细胞死亡和减少了细胞内生长.
- 在口腔感染期间,胆囊中胺的可用性限制了dthyA在口腔感染期间的生长.
- 降低的c-di-AMP水平在两种感染模型中都消除了ΔthyA的传染性.
- 当c-di-AMP水平较低时,c-di-AMP结合蛋白 PstA 调解细菌细胞死亡;其删除挽救了 ΔthyA 突变.
结论:
- 一个新的TLD调节机制由c-di-AMP在Lm已经确定.
- c-di-AMP作为TLD的关键抑制剂,影响感染期间的细菌生存.
- 针对抗叶酸和c-di-AMP通路,可能为菌病提供协同治疗策略.
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