主体通路的药理抑制增强了巨细胞杀死细胞内细菌病原体的作用
bioRxiv : the preprint server for biology
|April 28, 2025
概括
用药物向特定的巨细胞蛋白可以增强杀死细胞内病原体,如结核菌菌. 这种方法恢复了巨细胞的功能,可以抵抗诸如结核病,军团病等感染.
科学领域:
- 免疫学 免疫学 免疫学
- 微生物学 微生物学
- 细胞生物学 细胞生物学
背景情况:
- 致病性细菌,如 Mycobacterium tuberculosis (Mtb) 通过防止菌体的酸化和与溶酶体的融合来逃避巨细胞的杀死.
- 由Mtb积累的细胞外聚酸盐 (polyP) 抑制了巨细胞体酸化和杀死细菌.
- 主体蛋白质参与polyP抑制Dictyostelium discoideum中的杀死细菌.
研究的目的:
- 研究Dictyostelium discoideum蛋白质的药理抑制是否可以增强巨杀死细胞内病原体.
- 确定抑制特定宿主蛋白对Mtb诱导的巨细胞功能变化的影响,包括细胞酸性,炎症标志物和自性.
主要方法:
- 人类Dictyostelium discoideum蛋白质的药理抑制,包括P2Y1受体,哺乳动物目标拉帕米辛 (mTOR) 和伊诺西六酸激酶.
- 用多P降解酶 (ScPPX) 和蛋白质酶抑制剂治疗Mtb感染的人类巨细胞.
- 在经过处理的巨细胞中,评估细菌杀死,胞体酸化,CD54和CD206表达,自和蛋白质体活性.
主要成果:
- 抑制特定的宿主蛋白质 (P2Y1受体,mTOR,内醇六酸激酶) 增强了人类巨细胞杀死Mtb,Legionella pneumophila和Listeria monocytogenes的作用.
- ScPPX和某些抑制剂逆转了Mtb诱导的菌体酸化,CD54表达和自的抑制,并在雌性巨细胞中增加了CD54表达.
- Mtb对蛋白质酶活性的抑制被一些,但不是所有测试的抑制剂逆转.
结论:
- 选择宿主蛋白的药理抑制可以恢复巨细胞的功能,并增强细胞内病原体的杀死.
- 针对参与细菌逃生机制的宿主因素提供了针对结核病,军团病和李斯特菌病等感染的潜在治疗策略.
- 这些发现表明,通过调节宿主对细胞内细菌感染的反应,可能有治疗途径.
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