Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence-determinant stability.
Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence-determinant stability.
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DOI：
10.1002/mbo3.55
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发表时间：
2013-02
期刊：
影响因子：
3.4
通讯作者：
Shaw, Lindsey N.
中科院分区：
文献类型：
--
作者：
Kolar, Stacey L.;Ibarra, J. Antonio;Rivera, Frances E.;Mootz, Joe M.;Davenport, Jessica E.;Stevens, Stanley M.;Horswill, Alexander R.;Shaw, Lindsey N.
金黄色葡萄球菌是一种高毒性和成功的病原体，导致各种疾病。最近，在健康受试者中观察到由社区相关的耐甲氧西林沙门氏菌引起的严重感染的增加。金黄色葡萄球菌（CA-MRSA）。CA-MRSA毒力增强的原因尚不清楚;然而，研究表明，这是由于agr调节的毒素（包括分泌的蛋白酶）分泌过多所致。在这项研究中，我们探索的贡献外切蛋白酶CA-MRSA致病突变缺乏所有10种酶。我们表明，它们是在富含肽的环境中生长所必需的，血清中，在抗菌肽（AMP）的存在下，并在人体血液中。我们还发现，细胞外蛋白酶是重要的抵抗吞噬人类白细胞。使用小鼠感染模型，我们揭示了蛋白酶在发病率和死亡率中的对比作用。在外切蛋白酶删除后，我们观察到脓肿形成减少，器官浸润过程中的损害。与此相反，我们观察到的蛋白酶无效株的高毒力的死亡率的背景下。这种二分法解释了蛋白质组学分析，这表明外切蛋白酶的毒力决定因素的稳定性的关键介质。具体地，在蛋白酶缺失后观察到分泌的（例如α-毒素、Psms、LukAB、LukE、PVL、Sbi、γ-溶血素）和表面相关的（例如ClfA+B、FnbA+B、IsdA、Spa）蛋白的丰度增加。总的来说，我们的研究结果提供了一个独特的洞察CA-MRSA感染的进展，分泌的蛋白水解酶的作用。
Staphylococcus aureus is a highly virulent and successful pathogen that causes a diverse array of diseases. Recently, an increase of severe infections in healthy subjects has been observed, caused by community-associated methicillin-resistant S. aureus (CA-MRSA). The reason for enhanced CA-MRSA virulence is unclear; however, work suggests that it results from hypersecretion of agr-regulated toxins, including secreted proteases. In this study, we explore the contribution of exo-proteases to CA-MRSA pathogenesis using a mutant lacking all 10 enzymes. We show that they are required for growth in peptide-rich environments, serum, in the presence of antimicrobial peptides (AMPs), and in human blood. We also reveal that extracellular proteases are important for resisting phagocytosis by human leukocytes. Using murine infection models, we reveal contrasting roles for the proteases in morbidity and mortality. Upon exo-protease deletion, we observed decreases in abscess formation, and impairment during organ invasion. In contrast, we observed hypervirulence of the protease-null strain in the context of mortality. This dichotomy is explained by proteomic analyses, which demonstrates exo-proteases to be key mediators of virulence-determinant stability. Specifically, increased abundance of both secreted (e.g. α-toxin, Psms, LukAB, LukE, PVL, Sbi, γ-hemolysin) and surface-associated (e.g. ClfA+B, FnbA+B, IsdA, Spa) proteins was observed upon protease deletion. Collectively, our findings provide a unique insight into the progression of CA-MRSA infections, and the role of secreted proteolytic enzymes.
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