State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research of the Ministry of Education, Institute of Zoonosis, and College of Veterinary Medicine, Jilin University, Changchun, 130062, China.
Vet Res. 2024 Apr 15;55(1):52. doi: 10.1186/s13567-024-01301-1.
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.
产气荚膜梭菌（C.perfringens）感染被认为是威胁食品安全和农业发展的最具挑战性问题之一。迄今为止，C.perfringens 与宿主之间相互作用的分子机制仍知之甚少。在这里，我们表明干扰素基因刺激物（STING）依赖性训练免疫通过 mTOR 信号保护免受 C.perfringens 感染。热灭活白念珠菌（HKCA）训练在 LPS 再刺激后可引起小鼠腹腔巨噬细胞（PM）中 TNF-α和 IL-6 的产生增加。尽管 HKCA 训练的 PM 产生的 TNF-α和 IL-6 水平降低，但事实证明训练免疫很重要，即 HKCA 训练导致在 C.perfringens 感染期间体内和体外的细菌吞噬能力和清除能力增强。有趣的是，HKCA 训练导致 STING 信号的激活。我们进一步证明 STING 激动剂 DMXAA 是训练免疫的强诱导剂，并赋予 PM 对 C.perfringens 感染的宿主抗性。重要的是，与更高的细菌负担相对应，在 HKCA 训练后缺乏 STING 时，细胞因子分泌、吞噬作用和细菌杀伤作用减少。同时，在 HKCA 或 DMXAA 训练下，AKT/mTOR/HIF1α 的高表达水平确实伴随着激活的 STING 信号。此外，用雷帕霉素抑制 mTOR 信号会减弱 HKCA 训练后野生型（WT）PM 对 LPS 和 C.perfringens 挑战的训练反应。此外，STING 缺陷 PM 表现出 mTOR 信号相关蛋白水平降低。总之，这些结果支持 STING 参与训练免疫，通过 mTOR 信号保护免受 C.perfringens 感染。
