Protein C inhibitor--a novel antimicrobial agent.
Protein C inhibitor--a novel antimicrobial agent.
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DOI：
10.1371/journal.ppat.1000698
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发表时间：
2009-12
期刊：
影响因子：
6.7
通讯作者：
Herwald H
中科院分区：
文献类型：
--
作者：
Malmström E;Mörgelin M;Malmsten M;Johansson L;Norrby-Teglund A;Shannon O;Schmidtchen A;Meijers JC;Herwald H
蛋白C抑制物(PCI)是一种肝素结合型丝氨酸蛋白酶抑制物，属于丝氨酸蛋白家族。在这里，我们描述了PCI对细菌病原体具有广泛的抗菌活性。这种能力是通过PCI与脂膜的相互作用来调节的，从而导致它们的通透性。阴性染色的电子显微镜显示，经皮冠状动脉介入治疗后，大肠杆菌或化脓性链球菌引起细胞膜破裂，细菌胞浆内容物外流，细菌被杀死。PCI的抗菌活性位于蛋白的肝素结合部位，跨越该区域的多肽被发现模拟pCI的抗菌活性，而不会引起真核细胞的裂解或膜破坏。最后，我们证明了当激活时，血小板可以在其表面组装PCI。由于血小板被招募到细菌感染的部位，这些结果可能解释了我们的发现，化脓性链球菌引起的坏死性筋膜炎患者的组织活检中PCI值增加。综上所述，我们的数据描述了经皮冠状动脉介入治疗在先天性免疫中的新功能。先天免疫系统是我们对抗入侵病原体的战斗中不可或缺的一部分。抗菌肽和蛋白质由于能够穿透细菌细胞壁而参与了这场战斗，最终会导致细菌胞质内容物的外流，从而有效地杀菌。蛋白C抑制物(PCI)是一种多功能的肝素结合丝氨酸，与许多病理疾病有关，包括严重的感染性疾病。在这里，我们表明，PCI是一种有效的抗菌剂，能够破坏细菌细胞壁，从而导致细菌死亡。我们的研究还表明，与许多其他抗菌肽相比，由于全长蛋白发挥了抗菌活性，因此不需要对pCI进行处理，我们提供的数据表明，pCI在严重链球菌感染患者的感染部位富含。
Protein C inhibitor (PCI) is a heparin-binding serine proteinase inhibitor belonging to the family of serpin proteins. Here we describe that PCI exerts broad antimicrobial activity against bacterial pathogens. This ability is mediated by the interaction of PCI with lipid membranes, which subsequently leads to their permeabilization. As shown by negative staining electron microscopy, treatment of Escherichia coli or Streptococcus pyogenes bacteria with PCI triggers membrane disruption followed by the efflux of bacterial cytosolic contents and bacterial killing. The antimicrobial activity of PCI is located to the heparin-binding site of the protein and a peptide spanning this region was found to mimic the antimicrobial activity of PCI, without causing lysis or membrane destruction of eukaryotic cells. Finally, we show that platelets can assemble PCI on their surface upon activation. As platelets are recruited to the site of a bacterial infection, these results may explain our finding that PCI levels are increased in tissue biopsies from patients suffering from necrotizing fasciitis caused by S. pyogenes. Taken together, our data describe a new function for PCI in innate immunity. The innate immune system is an integral part of our battle against an invading pathogen. Antimicrobial peptides and proteins partake in this fight due to their ability to perforate the bacterial cell wall, which eventually will cause the efflux of bacterial cytosolic content and efficient bacterial killing. Protein C inhibitor (PCI) is a multifunctional heparin-binding serpin which has been implicated in a number of pathological conditions, including severe infectious diseases. Here we show that PCI is a potent antimicrobial agent that is able to destroy the bacterial cell wall and thereby cause death of the bacteria. Our study also shows that in contrast to many other antimicrobial peptides, processing of PCI is not required since the full length protein exerts its antimicrobial activity, and we present data demonstrating that PCI is enriched at the infected site of patients suffering from severe streptococcal infection.
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