Mapping of Interactions between Human Macrophages and Staphylococcus aureus Reveals an Involvement of MAP Kinase Signaling in the Host Defense

Staphylococcus aureus is a dangerous opportunistic human pathogen that causes serious invasive diseases when it reaches the bloodstream. Recent studies have shown that S. aureus is highly resistant to killing by professional phagocytes and that such cells even provide a favorable environment for intracellular survival of S. aureus. Importantly, the reciprocal interactions between phagocytes and S. aureus have remained largely elusive. Here we have employed kinase profiling to define the nature and time resolution of the human THP-1 macrophage response toward S. aureus and proteomics to identify the response of S. aureus toward macrophages. The results of these studies reveal major macrophage signaling pathways triggered by S. aureus and proteomic signatures of the responses of S. aureus to macrophages. We also identify human proteins bound to S. aureus that have potential roles in bacterial killing and internalization. Most noticeably, our observations challenge the classical concept that macrophage responses are mainly mediated through Toll-like receptor 2 and NF-κB signaling and highlight the important role of the stress-activated MAP kinase signaling in orchestrating the host defense.

金黄色葡萄球菌是一种危险的机敏性人类病原体，当其侵入血流时，可引发严重的侵袭性疾病。近期研究显示，金黄色葡萄球菌对专业吞噬细胞的杀伤具有高度耐药性，甚至为金黄色葡萄球菌在细胞内的存活提供了有利条件。值得注意的是，吞噬细胞与金黄色葡萄球菌之间的相互作用一直鲜有揭示。本研究采用激酶谱分析技术，以界定人类THP-1巨噬细胞对金黄色葡萄球菌反应的本质及其时间分辨率，并运用蛋白质组学技术，以识别金黄色葡萄球菌对巨噬细胞的反应。这些研究结果揭示了由金黄色葡萄球菌触发的巨噬细胞主要信号通路及其对巨噬细胞反应的蛋白质组学特征。此外，我们还确定了与金黄色葡萄球菌结合并可能参与细菌杀伤和内化的人类蛋白质。尤为引人注目的是，我们的观察结果对巨噬细胞反应主要通过Toll样受体2和NF-κB信号介导的经典观念提出了挑战，并突出了应激激活的MAP激酶信号在协调宿主防御中的重要作用。