Peptidoglycan Branched Stem Peptides Contribute to Streptococcus pneumoniae Virulence by Inhibiting Pneumolysin Release.
Peptidoglycan Branched Stem Peptides Contribute to Streptococcus pneumoniae Virulence by Inhibiting Pneumolysin Release.
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DOI：
10.1371/journal.ppat.1004996
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发表时间：
2015-06
期刊：
影响因子：
6.7
通讯作者：
Camilli A
中科院分区：
文献类型：
--
作者：
Greene NG;Narciso AR;Filipe SR;Camilli A
肺炎链球菌（肺炎球菌）定植于人类鼻咽部，是世界范围内的重要病原体。肺炎球菌溶血素 (Ply) 是一种由该生物体产生的多功能细胞外毒力因子，对于发病机制至关重要。尽管不存在任何明显的分泌或细胞表面附着基序，Ply 仍定位于活跃生长细胞的细胞包膜。我们试图描述这种表面定位的后果。通过对全细胞和亚细胞部分进行功能测定，我们确定 Ply 活性及其向细胞外环境的释放受到肽聚糖 (PG) 结构的抑制。 PG 抑制 Ply 释放的能力取决于该大分子的茎肽组成，该组成是通过编码负责分支茎肽合成的蛋白质的 murMN 操纵子的突变来操纵的。此外，从细胞表面去除胆碱结合蛋白显着降低了 Ply 的释放，达到在具有高比例分支茎肽的突变体中观察到的水平，表明这种结构特征与参与 PG 代谢的表面相关胆碱结合蛋白之间存在联系。与临床相关的是，我们还证明与青霉素耐药性相关的过度活跃的嵌合 murMN 等位基因会导致 Ply 释放减少，同时分支茎肽数量增加。最后，使用 murMN 缺失突变体，我们观察到 Ply 释放的增加对小鼠肺炎模型中的毒力有害。综上所述，我们的结果揭示了支链茎肽在肺炎球菌发病机制中的新作用，并证明了感染期间控制 Ply 释放的重要性。这些结果强调了 PG 组成在发病机制中的重要性，并且可能对在其他细菌病原体中观察到的不同 PG 结构具有广泛的影响。肺炎链球菌溶血素 (Ply) 是一种由肺炎链球菌产生的蛋白质毒素，有助于该微生物引起侵袭性疾病。这种蛋白质从细菌细胞中的释放对于其许多功能是必要的，但驱动这一过程的潜在机制尚未得到很好的表征。先前的研究表明 Ply 定位于细胞壁隔室。在这里，我们解决了这种定位的后果，并揭示了主要细胞壁结构成分肽聚糖在抑制 Ply 活性和释放到细胞外环境中的作用。肽聚糖是包裹细胞的一种重要的网状囊，影响其成分的改变会导致 Ply 释放量的差异。分子如何与细胞壁的限制性基质及其相关结构相互作用并穿过其，目前尚不完全清楚，特别是在蛋白质分泌和表面附着方面。我们的结果表明，细胞壁相关 Ply 的正确维护依赖于表面结构，并且可能对肺炎链球菌发病机制至关重要。
Streptococcus pneumoniae (the pneumococcus) colonizes the human nasopharynx and is a significant pathogen worldwide. Pneumolysin (Ply) is a multi-functional, extracellular virulence factor produced by this organism that is critical for pathogenesis. Despite the absence of any apparent secretion or cell surface attachment motifs, Ply localizes to the cell envelope of actively growing cells. We sought to characterize the consequences of this surface localization. Through functional assays with whole cells and subcellular fractions, we determined that Ply activity and its release into the extracellular environment are inhibited by peptidoglycan (PG) structure. The ability of PG to inhibit Ply release was dependent on the stem peptide composition of this macromolecule, which was manipulated by mutation of the murMN operon that encodes proteins responsible for branched stem peptide synthesis. Additionally, removal of choline-binding proteins from the cell surface significantly reduced Ply release to levels observed in a mutant with a high proportion of branched stem peptides suggesting a link between this structural feature and surface-associated choline-binding proteins involved in PG metabolism. Of clinical relevance, we also demonstrate that a hyperactive, mosaic murMN allele associated with penicillin resistance causes decreased Ply release with concomitant increases in the amount of branched stem peptides. Finally, using a murMN deletion mutant, we observed that increased Ply release is detrimental to virulence during a murine model of pneumonia. Taken together, our results reveal a novel role for branched stem peptides in pneumococcal pathogenesis and demonstrate the importance of controlled Ply release during infection. These results highlight the importance of PG composition in pathogenesis and may have broad implications for the diverse PG structures observed in other bacterial pathogens. Pneumolysin (Ply) is a protein toxin produced by Streptococcus pneumoniae that contributes to the ability of this organism to cause invasive disease. Release of this protein from the bacterial cell is necessary for many of its functions but the underlying mechanisms driving this process are not well characterized. Previous research demonstrated that Ply localizes to the cell wall compartment. Here, we address the consequences of this localization and reveal a role for the major cell wall structural component, peptidoglycan, in inhibiting Ply activity and release into the extracellular environment. Peptidoglycan is an essential, mesh-like sac that encases the cell, and alterations affecting its composition lead to differences in the amount of Ply released. How molecules interact with and traverse through the restrictive matrix of the cell wall and its associated structures is incompletely understood, particularly with respect to protein secretion and surface attachment. Our results argue that proper maintenance of cell wall-associated Ply is dependent on surface architecture and may be critical for S. pneumoniae pathogenesis.
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影响因子：
3.1
作者：
BERRY, AM;YOTHER, J;PATON, JC
通讯作者：
PATON, JC
影响因子：
3.2
作者：
Barendt, Skye M.;Sham, Lok-To;Winkler, Malcolm E.
通讯作者：
Winkler, Malcolm E.
影响因子：
2.1
作者：
Bricker, AL;Camilli, A
通讯作者：
Camilli, A
DOI：
10.1073/pnas.87.14.5415
发表时间：
1990-07-01
影响因子：
11.1
作者：
GARCIABUSTOS, J;TOMASZ, A
通讯作者：
TOMASZ, A
研究肺炎球菌类型的诱导物质转化的化学性质：通过从III型肺炎球菌分离出的脱氧核糖核酸分数诱导转化。
DOI：
10.1084/jem.79.2.137
发表时间：
1944-02-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Avery OT;Macleod CM;McCarty M
通讯作者：
McCarty M