Inflammation Program, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Veterans Administration Medical Center, Iowa City, IA 52240;
J Immunol. 2014 May 15;192(10):4709-17. doi: 10.4049/jimmunol.1302692. Epub 2014 Apr 11.
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) pose a significant threat to human health. Polymorphonuclear leukocytes (PMN) are the first responders during staphylococcal infection, but 15-50% of the initial ingested inoculum survives within the PMN phagosome and likely contributes directly or indirectly to disease pathogenesis. We hypothesize that surviving intracellular CA-MRSA undermine effective phagocyte-mediated defense by causing a decrease in macrophage uptake of PMN containing viable S. aureus and by promoting PMN lysis. In support of this hypothesis, PMN harboring viable CA-MRSA strain USA300 (PMN-SA) upregulated the "don't eat me" signal CD47, remained bound to the surface, and were inefficiently ingested by macrophages. In addition, coculture with PMN-SA altered the macrophage phenotype. Compared to macrophages fed USA300 alone, macrophages challenged with PMN-SA produced more IL-8 and less IL-1 receptor antagonist, TNF-α, activated caspase-1, and IL-1β. Although they exhibited some features of apoptosis within 3 h following ingestion of S. aureus, including phosphatidylserine exposure and mitochondrial membrane depolarization, PMN-SA had sustained levels of proliferating cell nuclear Ag expression, absence of caspase activation, and underwent lysis within 6 h following phagocytosis. PMN lysis was dependent on receptor-interacting protein 1, suggesting that PMN-SA underwent programmed necrosis or necroptosis. These data are the first demonstration, to our knowledge, that bacteria can promote sustained expression of proliferating cell nuclear Ag and that human PMN undergo necroptosis. Together, these findings demonstrate that S. aureus surviving within PMN undermine the innate immune response and may provide insight into the pathogenesis of S. aureus disease.
社区获得性耐甲氧西林金黄色葡萄球菌（CA-MRSA）对人类健康构成重大威胁。多形核白细胞（PMN）是金黄色葡萄球菌感染时的第一道防线，但 15-50%的初始摄入菌落在 PMN 吞噬体中存活下来，可能直接或间接导致疾病的发生。我们假设，存活的细胞内 CA-MRSA 通过降低巨噬细胞对含有活金黄色葡萄球菌的 PMN 的摄取，并促进 PMN 裂解，从而破坏有效的吞噬细胞介导的防御。支持这一假说，PMN 中携带活的 CA-MRSA 菌株 USA300（PMN-SA）上调了“不要吃我”信号 CD47，仍然与表面结合，并被巨噬细胞低效摄取。此外，与 PMN-SA 的共培养改变了巨噬细胞表型。与单独用 USA300 喂养的巨噬细胞相比，与 PMN-SA 共孵育的巨噬细胞产生更多的 IL-8 和更少的 IL-1 受体拮抗剂、TNF-α、激活的 caspase-1 和 IL-1β。尽管在摄入金黄色葡萄球菌后 3 小时内，PMN-SA 表现出一些凋亡特征，包括磷脂酰丝氨酸暴露和线粒体膜去极化，但 PMN-SA 持续表达增殖细胞核抗原，缺乏半胱氨酸天冬氨酸蛋白酶激活，在吞噬后 6 小时内发生裂解。PMN 裂解依赖于受体相互作用蛋白 1，表明 PMN-SA 经历了程序性坏死或坏死性凋亡。这些数据是我们所知的第一个证明细菌可以促进增殖细胞核抗原持续表达的证据，并且人类 PMN 经历了坏死性凋亡。这些发现表明，在 PMN 中存活的金黄色葡萄球菌破坏了先天免疫反应，并可能为金黄色葡萄球菌病的发病机制提供新的认识。
