infection entails a cascade of attacks and defence measures. After breaching the intestinal epithelial barrier, is phagocytosed by macrophages, where the bacteria encounter multiple stresses, to which it employs relevant countermeasures. Our study shows that, in , the polyamine spermidine activates a stress response mechanism by regulating critical antioxidant genes. Typhimurium mutants for spermidine transport and synthesis cannot mount an antioxidative response, resulting in high intracellular ROS levels. These mutants are also compromised in their ability to be phagocytosed by macrophages. Furthermore, it regulates a novel enzyme in , Glutathionyl-spermidine synthetase (GspSA), which prevents the oxidation of proteins in . Moreover, the spermidine mutants and the GspSA mutant show significantly reduced survival in the presence of hydrogen peroxide and reduced organ burden in the mouse model of infection. Conversely, in macrophages isolated from mice, we observed a rescue in the attenuated fold proliferation previously observed upon infection. We found that upregulates polyamine biosynthesis in the host through its effectors from SPI-1 and SPI-2, which addresses the attenuated proliferation observed in spermidine transport mutants. Thus, inhibition of this pathway in the host abrogates the proliferation of Typhimurium in macrophages. From a therapeutic perspective, inhibiting host polyamine biosynthesis using an FDA-approved chemopreventive drug, D, L-α-difluoromethylornithine (DFMO), reduces colonisation and tissue damage in the mouse model of infection while enhancing the survival of infected mice. Therefore, our work provides a mechanistic insight into the critical role of spermidine in stress resistance of . It also reveals a bacterial strategy in modulating host metabolism to promote their intracellular survival and shows the potential of DFMO to curb S infection.

中文翻译：

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鼠伤寒沙门氏菌利用亚精胺来对抗 ROS 介导的细胞毒性，并重新连接宿主多胺代谢以改善其在巨噬细胞中的存活


感染需要一系列的攻击和防御措施。突破肠上皮屏障后，被巨噬细胞吞噬，细菌遇到多重应激，并采取相应的应对措施。我们的研究表明，多胺亚精胺通过调节关键的抗氧化基因来激活应激反应机制。用于亚精胺转运和合成的鼠伤寒突变体不能产生抗氧化反应，导致细胞内活性氧水平升高。这些突变体被巨噬细胞吞噬的能力也受到损害。此外，它还调节 谷胱甘肽亚精胺合成酶 (GspSA) 中的一种新型酶，该酶可防止 中蛋白质的氧化。此外，亚精胺突变体和GspSA突变体在过氧化氢存在下表现出显着降低的存活率，并减少了小鼠感染模型中的器官负担。相反，在从小鼠体内分离的巨噬细胞中，我们观察到先前在感染时观察到的减弱的倍数增殖得到了挽救。我们发现，它通过 SPI-1 和 SPI-2 的效应子上调宿主体内的多胺生物合成，从而解决了在亚精胺转运突变体中观察到的增殖减弱问题。因此，抑制宿主中的这条途径可以消除巨噬细胞中鼠伤寒菌的增殖。从治疗角度来看，使用 FDA 批准的化学预防药物 D,L-α-二氟甲基鸟氨酸 (DFMO) 抑制宿主多胺生物合成，可以减少感染小鼠模型中的定植和组织损伤，同时提高受感染小鼠的存活率。因此，我们的工作为亚精胺在抗逆性中的关键作用提供了机制上的见解。 它还揭示了细菌调节宿主代谢以促进其细胞内存活的策略，并显示了 DFMO 抑制 S 感染的潜力。