Mapping of Interactions between Human Macrophages and <i>Staphylococcus aureus</i> 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（Staphylococcus aureus）是一种危险的机会致病性人类病原菌，当侵入血流时可引发严重的侵袭性疾病。近期研究显示，S. aureus对专职吞噬细胞的杀伤作用具有高度抗性，甚至这类细胞可为其胞内存活提供有利环境。尤为关键的是，吞噬细胞与S. aureus之间的双向互作机制在很大程度上仍未明确。本研究通过激酶谱分析，明确了人类THP-1巨噬细胞针对S. aureus的应答特征与时序分辨率，并借助蛋白质组学技术鉴定了S. aureus针对巨噬细胞的应答情况。上述研究结果揭示了S. aureus触发的核心巨噬细胞信号通路，以及S. aureus针对巨噬细胞应答的蛋白质组特征。本研究还鉴定出了与S. aureus结合的人类蛋白质，这类蛋白在细菌杀伤与内化过程中可能发挥潜在作用。最值得关注的是，我们的研究结果挑战了“巨噬细胞应答主要通过Toll样受体2（Toll-like receptor 2）与NF-κB信号通路介导”的经典认知，并凸显了应激激活的丝裂原活化蛋白激酶（stress-activated MAP kinase）信号通路在调控宿主防御中的核心作用。