CD9 co-operation with syndecan-1 is required for a major staphylococcal adhesion pathway
CD9 co-operation with syndecan-1 is required for a major staphylococcal adhesion pathway
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主要葡萄球菌粘附途径需要 CD9 与 syndecan-1 合作
DOI：
10.1101/2023.01.17.524294
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Green L
中科院分区：
文献类型：
--
作者：
Green L
上皮定植是细菌发病机制中关键的第一步。金黄色葡萄球菌可以利用多种宿主因子与细胞结合，包括 α5β1 整合素和硫酸乙酰肝素蛋白聚糖，例如多配体聚糖。在这里，我们证明整合素和多配体聚糖的伙伴蛋白，即宿主膜接头蛋白四跨膜蛋白 CD9，对于多配体聚糖介导的葡萄球菌粘附至关重要。纤连蛋白在此过程中也至关重要，而整合素仅对于粘附后进入人类上皮细胞至关重要。用 CD9 衍生肽或肝素处理上皮细胞会导致葡萄球菌粘附显着减少，这取决于 CD9 和 syndecan-1。外源性纤连蛋白引起葡萄球菌粘附的CD9依赖性增加，而β1整合素的阻断并不影响粘附，但确实减少了粘附细菌随后的内化。 CD9 破坏或缺失增加了 β1 整合素介导的内化，表明 CD9 协调顺序葡萄球菌粘附和内化。 CD9 通过 syndecan-1 控制葡萄球菌粘附，其机制可能需要 CD9 介导的 Syndecan 组织才能在宿主细胞表面正确展示纤连蛋白。我们建议可以开发 CD9 衍生肽或肝素类似物作为抗粘附治疗，以抑制葡萄球菌发病的初始阶段。重要性金黄色葡萄球菌感染是疾病和发病的重要原因。葡萄球菌利用多种粘附途径与上皮细胞结合，包括通过纤连蛋白桥与蛋白聚糖或 β1 整合素相互作用。尽管 CD9 不直接与细菌相互作用，但干扰另一种宿主蛋白四跨膜蛋白 CD9 会使葡萄球菌对上皮细胞的粘附减半。在这里，我们定义了 CD9 在葡萄球菌粘附和摄取中的作用，观察到 CD9 协调 Syndecan-1、纤连蛋白和 β1 整合素以实现有效的葡萄球菌感染。破坏这种作用的两种治疗方法是有效的，并且可以提供抗生素的替代品。我们深入了解了葡萄球菌感染宿主细胞的机制，首次通过 CD9 将两种已知的粘附途径连接在一起。
Epithelial colonization is a critical first step in bacterial pathogenesis.Staphylococcus aureuscan utilize several host factors to associate with cells, including α5β1 integrin and heparan sulfate proteoglycans, such as the syndecans. Here, we demonstrate that a partner protein of both integrins and syndecans, the host membrane adapter protein tetraspanin CD9, is essential for syndecan-mediated staphylococcal adhesion. Fibronectin is also essential in this process, while integrins are only critical for post-adhesion entry into human epithelial cells. Treatment of epithelial cells with CD9-derived peptide or heparin caused significant reductions in staphylococcal adherence, dependent on both CD9 and syndecan-1. Exogenous fibronectin caused a CD9-dependent increase in staphylococcal adhesion, whereas blockade of β1 integrins did not affect adhesion but did reduce the subsequent internalization of adhered bacteria. CD9 disruption or deletion increased β1 integrin-mediated internalization, suggesting that CD9 coordinates sequential staphylococcal adhesion and internalization. CD9 controls staphylococcal adhesion through syndecan-1, using a mechanism that likely requires CD9-mediated syndecan organization to correctly display fibronectin at the host cell surface. We propose that CD9-derived peptides or heparin analogs could be developed as anti-adhesion treatments to inhibit the initial stages of staphylococcal pathogenesis.IMPORTANCEStaphylococcus aureusinfection is a significant cause of disease and morbidity.Staphylococciutilize multiple adhesion pathways to associate with epithelial cells, including interactions with proteoglycans or β1 integrins through a fibronectin bridge. Interference with another host protein, tetraspanin CD9, halves staphylococcal adherence to epithelial cells, although CD9 does not interact directly with bacteria. Here, we define the role of CD9 in staphylococcal adherence and uptake, observing that CD9 coordinates syndecan-1, fibronectin, and β1 integrins to allow efficient staphylococcal infection. Two treatments that disrupt this action are effective and may provide an alternative to antibiotics. We provide insights into the mechanisms that underlie staphylococcal infection of host cells, linking two known adhesion pathways together through CD9 for the first time.
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影响因子：
3.7
作者：
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7.2
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