Staphylococcus aureus Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages.
Staphylococcus aureus Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages.
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DOI：
10.1128/mbio.01143-18
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发表时间：
2018-07-17
期刊：
影响因子：
6.4
通讯作者：
Heinrichs DE
中科院分区：
文献类型：
--
作者：
Flannagan RS;Kuiack RC;McGavin MJ;Heinrichs DE
巨噬细胞由于具有吞噬细菌的能力，对于先天免疫至关重要。巨噬细胞吞噬溶酶体是一种高酸性细胞器，具有有效的抗菌特性，但值得注意的是，摄入的金黄色葡萄球菌会在这个生态位中复制。在此，我们证明金黄色葡萄球菌需要 GraXRS 调节系统才能在该生态位内生长，而 SaeRS 和 AgrAC 双组分调节系统以及 α-苯酚可溶性调节蛋白是可有可无的。重要的是，我们发现，金黄色葡萄球菌在完全酸化的巨噬细胞吞噬溶酶体内最佳生长需要暴露在酸性 pH 值下。金黄色葡萄球菌暴露于酸性 pH 条件下会引发 GraS 信号传导，进而引发适应性反应，从而增强细菌对巨噬细胞吞噬溶酶体内遇到的抗菌效应物（例如抗菌肽）的抵抗力。值得注意的是，金黄色葡萄球菌中 pH 依赖性抗菌肽耐药性的诱导需要 GraS 传感器激酶。 GraS 和 MprF 是 GraS 调节子的成员，在全身感染的急性阶段对细菌的存活发挥着重要作用，在小鼠感染模型中，金黄色葡萄球菌存在于肝脏库普弗细胞内。我们得出的结论是，GraXRS 代表了一个重要的调节系统，其功能是让金黄色葡萄球菌在宿主抗菌免疫细胞内复制开始之前逃避杀伤。金黄色葡萄球菌可以感染身体的任何部位，包括巨噬细胞的杀菌吞噬溶酶体。金黄色葡萄球菌感染不同生态位的能力要求细菌具有高度适应性。在这里，我们表明金黄色葡萄球菌对吞噬溶酶体酸化作出反应，引起基因表达的变化，使细菌能够抵抗吞噬溶酶体杀伤并促进复制。对于这种反应来说，毒素的产生是可有可无的。然而，细菌需要传感器激酶 GraS，它可以响应酸性 pH 值而转导信号。 GraS 对于金黄色葡萄球菌在全身感染急性期的吞噬溶酶体复制和存活是必需的。金黄色葡萄球菌适应的破坏将使金黄色葡萄球菌容易受到吞噬细胞的限制。
Macrophages are critical to innate immunity due to their ability to phagocytose bacteria. The macrophage phagolysosome is a highly acidic organelle with potent antimicrobial properties, yet remarkably, ingested Staphylococcus aureus replicates within this niche. Herein we demonstrate that S. aureus requires the GraXRS regulatory system for growth within this niche, while the SaeRS and AgrAC two-component regulatory systems and the α-phenol soluble modulins are dispensable. Importantly, we find that it is exposure to acidic pH that is required for optimal growth of S. aureus inside fully acidified macrophage phagolysosomes. Exposure of S. aureus to acidic pH evokes GraS signaling, which in turn elicits an adaptive response that endows the bacteria with increased resistance to antimicrobial effectors, such as antimicrobial peptides, encountered inside macrophage phagolysosomes. Notably, pH-dependent induction of antimicrobial peptide resistance in S. aureus requires the GraS sensor kinase. GraS and MprF, a member of the GraS regulon, play an important role for bacterial survival in the acute stages of systemic infection, where in murine models of infection, S. aureus resides within liver-resident Kupffer cells. We conclude that GraXRS represents a vital regulatory system that functions to allow S. aureus to evade killing, prior to commencement of replication, within host antibacterial immune cells. S. aureus can infect any site of the body, including the microbicidal phagolysosome of the macrophage. The ability of S. aureus to infect diverse niches necessitates that the bacteria be highly adaptable. Here we show that S. aureus responds to phagolysosome acidification to evoke changes in gene expression that enable the bacteria to resist phagolysosomal killing and to promote replication. Toxin production is dispensable for this response; however, the bacteria require the sensor kinase GraS, which transduces signals in response to acidic pH. GraS is necessary for phagolysosomal replication and survival of S. aureus in the acute stage of systemic infection. Disruption of this S. aureus adaptation would render S. aureus susceptible to phagocyte restriction.