基于表观遗传和免疫代谢调控的训练固有免疫记忆在新生儿脓毒症中的作用机制研究

Neonates are more susceptible to microbial infection and sepsis due to their well-described defects in innate immune responses and functions. This proposed research project attempts to address the scientific question of whether training innate immunity boosts the inflammatory response and antimicrobial capacity in neonates, and the underlying mechanisms involved. In our preliminary experiments, we found that stimulation of neonate murine macrophages with BCG plus BLP led to the induction of trained innate immunity characterized by augmented both inflammatory and antimicrobial responses, which is closely associated with histone modification-induced epigenetic reprogramming (the upregulated H3K4me3 and suppressed H3K9me3) and the shift of cellular metabolic pathways (the increased glycolysis). The specific objectives of this project are: 1).whether training innate immunity in neonates leads to boosted inflammatory and antimicrobial responses, thus conferring the protection against microbial sepsis-associated lethality; 2).whether epigenetic reprogramming is the underlying mechanism responsible for the boosting of inflammatory and antimicrobial responses; 3).whether training innate immunity-induced shift in cellular metabolism contributes to epigenetic reprogramming; 4).whether training innate immunity in monocytes from full-term healthy newborns leads to augmented inflammatory response and antimicrobial capacity compared with premature birth and vary low-birth-weight neonates. Thus, we aimed to elucidate the interlink and mechanism(s) by which epigenetic reprogramming and cellular metabolism shifting modulate trained innate immune memory, in order to explore and discover new strategies for preventing and treating neonatal sepsis.

新生儿存在固有免疫应答低下和功能缺陷而对细菌感染和脓毒症易感性增高。本项目聚焦的科学问题是：训练固有免疫记忆调控新生儿固有免疫介导的炎症反应和抗菌能力的作用机制。我们预初实验研究发现，应用卡介苗（BCG）和细菌脂蛋白（BLP）可诱导新生儿产生以炎症反应和抗菌活性同时增强为特征的固有免疫记忆，其与组蛋白修饰引起的表观遗传重编程和糖酵解代谢调控相关。鉴此，本项目拟以训练新生儿固有免疫记忆为切入点，研究：1.BCG+BLP训练固有免疫记忆防治脓毒症的作用；2.训练固有免疫记忆调控组蛋白修饰诱导表观遗传重编程增强炎症反应和抗菌活性的机制；3.训练固有免疫记忆诱导细胞代谢途径移位对遗传表观重编程的影响；4.临床评估训练固有免疫记忆提高新生儿、早产和低体重儿抗感染能力的作用。籍此，阐明基于表观遗传和免疫代谢调控的训练固有免疫记忆的作用机制，探索和形成防治新生儿脓毒症的新策略。

新生儿脓毒症发生发展的病理过程和分子机制是新生儿和儿科重症医学亟需解决的问题。新生儿对感染炎症反应的不足和保护性免疫应答的缺陷，导致新生儿对感染的风险增加以及清除感染的能力降低。因此，如何增强新生儿感染后产生有效的炎症反应以及增强其清除感染的能力成为目前人们研究关注的焦点。近年来研究发现，训练免疫通过调控表观遗传和细胞代谢，可激发和增强成人固有免疫细胞对再次感染的炎症反应；而我们的实验结果表明，应用BCG（卡介疫苗）和BLP（细菌脂蛋白）可以诱导新生儿产生以炎症反应和抗菌活性同时增强为特征的固有免疫记忆。以BCG和BLP联合应用为手段，能够激发一种既能促进新生儿炎症反应又能增强抗菌能力的固有免疫记忆细胞；阐明BCG+BLP训练免疫可能通过激活和诱发细胞代谢途径移位来调控组蛋白表观遗传修饰进而促进了在炎症和抗菌中起关键作用的分子转录；最终达到提高新生儿固有免疫细胞的炎症反应和杀菌功能。本项目研究结论不仅在基础理论上阐明训练固有免疫记忆形成的机制，同时能为临床治疗新生儿感染提供有效的治疗措施。