Wang Xiao, Zhang Fuhua, Dai Qianqi, Zhao Yixin, Liu Mohua, Wu Conghui, Tang Jingjing, Gu Yanchao, Xie Zhen, Chen Shukun, Zhang Mengsi, Luo Chunhui, Wang Xiao, Wang Yao, Shen Xihui, Xu Lei
State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, PR China.
Cytokine. 2025 Oct;194:157009. doi: 10.1016/j.cyto.2025.157009. Epub 2025 Aug 12.
Manganese (Mn) is an important element in bacteria-host interactions, exerting significant functions on both bacterial physiology and host immune responses. The importance of bacterial Mn transport systems in mediating bacterial stress resistance has been recognized, however, its role in modulating host innate immunity during infections remained elusive. This study aimed to explore the functions of the Mn transport proteins MntH and SitABCD in two enteric pathogens, Enterohemorrhagic Escherichia coli (EHEC) and Salmonella enterica serovar Typhimurium. We demonstrate that mutants deficient in these Mn uptake transporters (EHEC ΔmntH and S. typhimurium ΔmntHΔsitA) exhibit markedly reduced resistance to extreme environmental conditions like oxidative stress and impaired competitive advantages. Importantly, EHEC ΔmntH and S. typhimurium ΔmntHΔsitA elicited a significantly stronger innate immune response in macrophages compared to wild-type strains, indicating that MntH and SitABCD play a crucial role in inhibiting host immune activation. Specifically, we observed that Mn enhanced the innate immune response to infection, and such an effect was abrogated in cGas and Sting macrophages. Importantly, MntH and SitABCD suppress innate immune response via the STING pathway. In conclusion, this study showed that the Mn transport systems in EHEC and S. typhimurium play important roles in modulating host immune responses, highlighting the importance of Mn availability in shaping the outcomes of enteropathogenic bacterial infections. IMPORTANCE: The manganese (Mn) transport systems MntH and SitABCD are crucial for bacterial survival. This study elucidates the role of Mn transport in enhancing bacterial resilience to oxidative stress and modulating the host's innate immune system, focusing on Enterohemorrhagic Escherichia coli (EHEC) and Salmonella enterica serovar Typhimurium. Our findings demonstrate that Mn uptake transporters not only confer stress resistance but also play a significant role in attenuating host immune activation through the STING signaling pathway. Mutants lacking MntH and SitABCD showed increased immune activation, suggesting these transporters help bacteria evade detection. The findings reveal that manganese not only enhances bacterial stress resistance but also modulates immune activation, thereby influencing infection outcomes.
锰（Mn）是细菌与宿主相互作用中的一种重要元素，对细菌生理学和宿主免疫反应均发挥着重要作用。细菌锰转运系统在介导细菌抗逆性方面的重要性已得到认可，然而，其在感染过程中调节宿主固有免疫的作用仍不明确。本研究旨在探究锰转运蛋白MntH和SitABCD在两种肠道病原体——肠出血性大肠杆菌（EHEC）和鼠伤寒沙门氏菌中的功能。我们证明，缺乏这些锰摄取转运蛋白的突变体（EHEC ΔmntH和鼠伤寒沙门氏菌ΔmntHΔsitA）对氧化应激等极端环境条件的抗性显著降低，且竞争优势受损。重要的是，与野生型菌株相比，EHEC ΔmntH和鼠伤寒沙门氏菌ΔmntHΔsitA在巨噬细胞中引发了明显更强的固有免疫反应，这表明MntH和SitABCD在抑制宿主免疫激活中起关键作用。具体而言，我们观察到锰增强了对感染的固有免疫反应，而在cGas和Sting巨噬细胞中这种效应被消除。重要的是，MntH和SitABCD通过STING途径抑制固有免疫反应。总之，本研究表明EHEC和鼠伤寒沙门氏菌中的锰转运系统在调节宿主免疫反应中起重要作用，凸显了锰的可利用性在决定肠道致病性细菌感染结果中的重要性。重要性：锰（Mn）转运系统MntH和SitABCD对细菌存活至关重要。本研究阐明了锰转运在增强细菌对氧化应激的恢复力以及调节宿主固有免疫系统方面的作用，重点关注肠出血性大肠杆菌（EHEC）和鼠伤寒沙门氏菌。我们的研究结果表明，锰摄取转运蛋白不仅赋予抗逆性，还通过STING信号通路在减弱宿主免疫激活中发挥重要作用。缺乏MntH和SitABCD的突变体显示出免疫激活增加，表明这些转运蛋白有助于细菌逃避检测。研究结果揭示，锰不仅增强细菌抗逆性，还调节免疫激活，从而影响感染结果。
