STING 依赖性训练免疫通过 mTOR 信号转导帮助宿主抵御产气荚膜梭菌感染

IF 3.7 1区 农林科学 Q1 VETERINARY SCIENCES
Zhen-Zhen Liu, Cheng-Kai Zhou, Xiao-Qi Lin, Yu Gao, Xue-Yue Luo, Jia-Bao Zhang, Qi Yin, Liang Zhang, Jian-Gang Zhang, Xin An, Wei Chen, Yong-Jun Yang
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引用次数: 0

摘要

产气荚膜梭菌(C. perfringens)感染被认为是威胁食品安全和困扰农业发展的最具挑战性的问题之一。迄今为止,人们对产气荚膜梭菌与宿主之间相互作用的分子机制仍然知之甚少。在这里,我们发现干扰素基因刺激因子(STING)依赖的训练有素的免疫通过 mTOR 信号转导来抵御 C. perfringens 感染。小鼠腹腔巨噬细胞(PM)在受到 LPS 再刺激后,热杀死的白色念珠菌(HKCA)训练会诱发 TNF-α 和 IL-6 的产生。虽然经过 HKCA 训练的 PM 产生的 TNF-α 和 IL-6 水平降低了,但 HKCA 训练增强了体内和体外 C. perfringens 感染期间的细菌吞噬能力和清除能力,这证明了训练免疫的重要性。有趣的是,HKCA 训练激活了 STING 信号传导。我们进一步证明,STING激动剂DMXAA是训练免疫的强诱导剂,能增强宿主对PM中C.perfringens感染的抵抗力。重要的是,HKCA训练后,在STING缺失的情况下,与较高的细菌负荷相对应,细胞因子分泌、吞噬能力和细菌杀伤力均有所下降。同时,在HKCA或DMXAA训练中,AKT/mTOR/HIF1α的高表达水平确实伴随着STING信号的激活。此外,用雷帕霉素抑制mTOR信号转导抑制了野生型(WT)PM在HKCA训练后对LPS和C. perfringens挑战的训练反应。此外,STING缺陷型PM的mTOR信号转导相关蛋白水平降低。总之,这些结果支持 STING 参与训练免疫,通过 mTOR 信号转导保护细胞免受 C. perfringens 感染。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
STING-dependent trained immunity contributes to host defense against Clostridium perfringens infection via mTOR signaling
Clostridium perfringens (C. perfringens) infection is recognized as one of the most challenging issues threatening food safety and perplexing agricultural development. To date, the molecular mechanisms of the interactions between C. perfringens and the host remain poorly understood. Here, we show that stimulator of interferon genes (STING)-dependent trained immunity protected against C. perfringens infection through mTOR signaling. Heat-killed Candida albicans (HKCA) training elicited elevated TNF-α and IL-6 production after LPS restimulation in mouse peritoneal macrophages (PM). Although HKCA-trained PM produced decreased levels of TNF-α and IL-6, the importance of trained immunity was demonstrated by the fact that HKCA training resulted in enhanced bacterial phagocytic ability and clearance in vivo and in vitro during C. perfringens infection. Interestingly, HKCA training resulted in the activation of STING signaling. We further demonstrate that STING agonist DMXAA is a strong inducer of trained immunity and conferred host resistance to C. perfringens infection in PM. Importantly, corresponding to higher bacterial burden, reduction in cytokine secretion, phagocytosis, and bacterial killing were shown in the absence of STING after HKCA training. Meanwhile, the high expression levels of AKT/mTOR/HIF1α were indeed accompanied by an activated STING signaling under HKCA or DMXAA training. Moreover, inhibiting mTOR signaling with rapamycin dampened the trained response to LPS and C. perfringens challenge in wild-type (WT) PM after HKCA training. Furthermore, STING‑deficient PM presented decreased levels of mTOR signaling-related proteins. Altogether, these results support STING involvement in trained immunity which protects against C. perfringens infection via mTOR signaling.
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来源期刊
Veterinary Research
Veterinary Research 农林科学-兽医学
CiteScore
7.00
自引率
4.50%
发文量
92
审稿时长
3 months
期刊介绍: Veterinary Research is an open access journal that publishes high quality and novel research and review articles focusing on all aspects of infectious diseases and host-pathogen interaction in animals.
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