Syndecan-1 Promotes Staphylococcus aureus Corneal Infection by Counteracting Neutrophil-mediated Host Defense
Syndecan-1 Promotes Staphylococcus aureus Corneal Infection by Counteracting Neutrophil-mediated Host Defense
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DOI：
10.1074/jbc.m110.185165
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发表时间：
2011-02-04
影响因子：
4.8
通讯作者：
Park, Pyong Woo
中科院分区：
文献类型：
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作者：
Hayashida, Atsuko;Amano, Shiro;Park, Pyong Woo
许多微生物病原体在体外破坏细胞表面硫酸乙酰肝素蛋白聚糖（HSPGs）以感染宿主细胞。然而，HSPG-病原体相互作用在体内的意义仍有待确定。在这项研究中，我们研究了syndecan-1，上皮细胞的主要细胞表面HSPG，在金黄色葡萄球菌角膜感染中的作用。我们发现syndecan-1 null（Sdc 1（-/-））小鼠显著抵抗S.金黄色葡萄球菌角膜感染与野生型（WT）小鼠相比，表达丰富的syndecan-1在他们的角膜上皮。然而，syndecan-1不与S. syndecan-1对培养的角膜上皮细胞的定殖没有影响。提示syndecan-1不介导S. aureus。金黄色葡萄球菌附着于体内角膜组织。相反，S.金黄色葡萄球菌诱导syndecan-1胞外域从角膜上皮细胞表面脱落。局部施用纯化的多配体蛋白聚糖-1胞外域或硫酸乙酰肝素（HS）显著增加，而抑制多配体蛋白聚糖-1脱落显著降低角膜组织中的细菌负荷。此外，耐药Sdc 1（-/-）小鼠中中性粒细胞的耗竭增加了敏感WT小鼠的角膜细菌负荷，表明syndecan-1调节中性粒细胞以促进感染。我们发现syndecan-1并不影响中性粒细胞向感染角膜的浸润，但纯化的syndecan-1胞外域和HS显著抑制嗜中性粒细胞介导的S.金黄色。这些数据表明了一种以前未知的细菌颠覆机制，其中S。金黄色葡萄球菌利用多配体蛋白聚糖-1胞外域以HS依赖性方式抑制嗜中性粒细胞介导的细菌杀伤机制的能力，以促进其在角膜中的发病机制。
Many microbial pathogens subvert cell surface heparan sulfate proteoglycans (HSPGs) to infect host cells in vitro. The significance of HSPG-pathogen interactions in vivo, however, remains to be determined. In this study, we examined the role of syndecan-1, a major cell surface HSPG of epithelial cells, in Staphylococcus aureus corneal infection. We found that syndecan-1 null (Sdc1(-/-)) mice significantly resist S. aureus corneal infection compared with wild type (WT) mice that express abundant syndecan-1 in their corneal epithelium. However, syndecan-1 did not bind to S. aureus, and syndecan-1 was not required for the colonization of cultured corneal epithelial cells by S. aureus, suggesting that syndecan-1 does not mediate S. aureus attachment to corneal tissues in vivo. Instead, S. aureus induced the shedding of syndecan-1 ectodomains from the surface of corneal epithelial cells. Topical administration of purified syndecan-1 ectodomains or heparan sulfate (HS) significantly increased, whereas inhibition of syndecan-1 shedding significantly decreased the bacterial burden in corneal tissues. Furthermore, depletion of neutrophils in the resistant Sdc1(-/-) mice increased the corneal bacterial burden to that of the susceptible WT mice, suggesting that syndecan-1 moderates neutrophils to promote infection. We found that syndecan-1 does not affect the infiltration of neutrophils into the infected cornea but that purified syndecan-1 ectodomain and HS significantly inhibit neutrophil-mediated killing of S. aureus. These data suggest a previously unknown bacterial subversion mechanism where S. aureus exploits the capacity of syndecan-1 ectodomains to inhibit neutrophil-mediated bacterial killing mechanisms in an HS-dependent manner to promote its pathogenesis in the cornea.