Staphylococcus aureus is among the leading causes of bacterial infections worldwide. The pathogenicity and establishment of S. aureus infections are tightly linked to its ability to modulate host immunity. Persistent infections are often associated with mutant staphylococcal strains that have decreased susceptibility to antibiotics; however, little is known about how these mutations influence bacterial interaction with the host immune system. Here, we discovered that clinical S. aureus isolates activate human monocytes, leading to cell-surface expression of immune stimulatory natural killer group 2D (NKG2D) ligands on the monocytes. We found that expression of the NKG2D ligand ULBP2 (UL16-binding protein 2) is associated with bacterial degradability and phagolysosomal activity. Moreover, S. aureus–induced ULBP2 expression was linked to altered host cell metabolism, including increased cytoplasmic (iso)citrate levels, reduced glycolytic flux, and functional mitochondrial activity. Interestingly, we found that the ability of S. aureus to induce ULBP2 and proinflammatory cytokines in human monocytes depends on a functional ClpP protease in S. aureus. These findings indicate that S. aureus activates ULBP2 in human monocytes through immunometabolic mechanisms and reveal that clpP inactivation may function as a potential immune evasion mechanism. Our results provide critical insight into the interplay between the host immune system and S. aureus that has evolved under the dual selective pressure of host immune responses and antibiotic treatment. Our discovery of an immune stimulatory pathway consisting of human monocyte-based defense against S. aureus suggests that targeting the NKG2D pathway holds potential for managing persistent staphylococcal infections.

中文翻译：

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金黄色葡萄球菌诱导人单核细胞上免疫刺激性 NKG2D 配体的细胞表面表达。

金黄色葡萄球菌是全世界细菌感染的主要原因之一。金黄色葡萄球菌感染的致病性和建立与其调节宿主免疫的能力密切相关。持续感染通常与对抗生素的敏感性降低的突变葡萄球菌菌株有关；然而，人们对这些突变如何影响细菌与宿主免疫系统的相互作用知之甚少。在这里，我们发现临床金黄色葡萄球菌分离物激活人类单核细胞，导致单核细胞上免疫刺激性自然杀伤组 2D (NKG2D) 配体的细胞表面表达。我们发现 NKG2D 配体 ULBP2（UL16 结合蛋白 2）的表达与细菌降解性和吞噬溶酶体活性有关。此外，S。金黄色葡萄球菌诱导的 ULBP2 表达与宿主细胞代谢改变有关，包括细胞质（异）柠檬酸盐水平增加、糖酵解通量降低和功能性线粒体活性。有趣的是，我们发现金黄色葡萄球菌在人单核细胞中诱导 ULBP2 和促炎细胞因子的能力取决于金黄色葡萄球菌中的功能性 ClpP 蛋白酶。这些发现表明，金黄色葡萄球菌通过免疫代谢机制激活人单核细胞中的 ULBP2，并揭示 clpP 失活可能起到潜在的免疫逃避机制的作用。我们的研究结果提供了对宿主免疫系统和金黄色葡萄球菌之间相互作用的重要见解，金黄色葡萄球菌在宿主免疫反应和抗生素治疗的双重选择压力下进化。