Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism
Staphylococcus aureus resists human defensins by production of staphylokinase, a novel bacterial evasion mechanism
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DOI：
10.4049/jimmunol.172.2.1169
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发表时间：
2004-01-15
影响因子：
4.4
通讯作者：
Tarkowski, A
中科院分区：
文献类型：
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作者：
Jin, T;Bokarewa, M;Tarkowski, A
α-防御素是由多形核细胞分泌的多肽，通过破坏细菌细胞壁的完整性来提供抗菌保护。葡激酶是金黄色葡萄球菌产生的一种外源蛋白，可激活宿主纤溶酶原。在这项研究中，我们分析了α-防御素和葡萄球菌激酶之间的相互作用对葡萄球菌生长的影响。我们观察到葡激酶诱导多形核细胞释放α-防御素。此外，α-防御素和葡激酶之间的直接结合被证明导致了复合体的形成。这种相互作用的生物学后果是几乎完全抑制了α-防御素的杀菌作用。值得注意的是，具有封闭的纤溶酶原结合部位的葡萄球菌酶仍能中和α-防御素的杀菌作用。相比之下，葡激酶分子第74位的单一突变，用赖氨酸取代丙氨酸，导致其α-防御素中和特性降低50%。在体外和金黄色葡萄球菌关节炎的小鼠模型中，对19株金黄色葡萄球菌进行了α-防御素的杀菌特性测试。产生葡激酶的葡萄球菌菌株可以抵抗α-防御素的杀菌作用。当将葡激酶加入金黄色葡萄球菌阴性的培养物中时，它几乎完全取消了α-防御素的作用。最后，与细菌一起关节内注射的人中性粒细胞多肽2减轻了关节的破坏。在这项研究中，我们报道了葡激酶的一种新特性，它能够诱导防御素的分泌，复合结合防御素，并中和它们的杀菌作用。因此，在金黄色葡萄球菌感染期间，葡激酶的产生可能与体内的防御素耐药有关。免疫学杂志，2004,172：1169-1176。
alpha-Defensins are peptides secreted by polymorphonuclear cells and provide antimicrobial protection mediated by disruption of the integrity of bacterial cell walls. Staphylokinase is an exoprotein produced by Staphylococcus aureus, which activates host plasminogen. In this study, we analyzed the impact of interaction between alpha-defensins and staphylokinase on staphylococcal growth. We observed that staphylokinase induced extracellular release of alpha-defensins from polymorphonuclear cells. Moreover, a direct binding between alpha-defensins and staphylokinase was shown to result in a complex formation. The biological consequence of this interaction was an almost complete inhibition of the bactericidal effect of alpha-defensins. Notably, staphylokinase with blocked plasminogen binding site still retained its ability to neutralize the bactericidal effect of alpha-defensins. In contrast, a single mutation of a staphylokinase molecule at position 74, substituting lysine for alanine, resulted in a 50% reduction of its alpha-defensin-neutralizing properties. The bactericidal properties of alpha-defensins were tested in 19 S. aureus strains in vitro and in a murine model of S. aureus arthritis. Staphylococcal strains producing staphylokinase were protected against the bactericidal effect of alpha-defensins. When staphylokinase was added to staphylokinase-negative S. aureus cultures, it almost totally abrogated the effect of alpha-defensins. Finally, human neutrophil peptide 2 injected intra-articularly along with bacteria alleviated joint destruction. In this study, we report a new property of staphylokinase, its ability to induce secretion of defensins, to complex bind them and to neutralize their bactericidal effect. Staphylokinase production may therefore be responsible in vivo for defensin resistance during S. aureus infections. The Journal of Immunology, 2004, 172: 1169-1176.