在LPS中,TCA代谢调节了DNA高甲基化和Mycobacterium结核病诱导的免疫耐受性
Abhimanyu1, Santiago Carrero Longlax1, Tomoki Nishiguchi1
1Department of Pediatrics, The Global TB Program, William T Shearer Center for Immunobiology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030.
概括
严重的感染会导致持久的表观遗传变化. 三碳酸 (TCA) 循环驱动这些DNA甲基化变化,但代谢药物可以减轻它们,提供一种新的治疗方法.
科学领域:
- 免疫学 免疫学 免疫学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
- 代谢途径 代谢途径
背景情况:
- 像结核病 (TB) 这样的严重感染会导致表观遗传变化,与死亡率的增加有关.
- 代谢途径,特别是三碳酸 (TCA) 循环,是瘤学中已知的表观遗传驱动因素.
- 在感染引起的免疫耐受性之后,TCA循环在表观遗传调节中的作用仍然不清楚.
研究的目的:
- 为了研究TCA循环是否调节感染诱导的免疫耐受性后的DNA甲基化.
- 为了确定代谢操纵是否可以减轻感染诱导的表观遗传变化.
主要方法:
- 利用脂多糖和Mycobacterium结核病模型来研究感染诱导的表观遗传变化.
- 评估了TCA循环抑制剂 (例如,异酸脱酶抑制剂) 和细胞代谢抑制剂 (例如,拉巴胺,恒,甲胺) 的影响.
- 研究了外源性TCA代谢物 (苏酸盐,伊塔康酸盐) 对DNA甲基化和免疫耐受性的影响.
- 在接受everolimus治疗的结核病患者中分析了DNA甲基化.
主要成果:
- 脂聚糖和Mycobacterium结核病诱导的DNA甲基化变化由TCA循环介导.
- 感染诱导的DNA高甲基化被细胞代谢和TCA循环抑制剂减少.
- 补充TCA代谢物 (succinate,itaconate) 导致DNA高甲基化和免疫耐受性.
- 接受埃弗罗利斯治疗的结核病患者显示DNA高甲基化减少.
结论:
- 在感染诱导的免疫耐受性之后,TCA循环在调节DNA甲基化方面发挥着至关重要的作用.
- 使用诸如Everolimus之类的抑制剂进行代谢操纵,可以有效地减轻感染诱导的表观遗传痕.
- 这些发现提供了针对代谢途径的概念证明,以解决感染后的发病率和死亡率.
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