Oral streptococci utilize a Siglec-like domain of serine-rich repeat adhesins to preferentially target platelet sialoglycans in human blood.
Oral streptococci utilize a Siglec-like domain of serine-rich repeat adhesins to preferentially target platelet sialoglycans in human blood.
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DOI：
10.1371/journal.ppat.1004540
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发表时间：
2014-12
期刊：
影响因子：
6.7
通讯作者：
Varki A
中科院分区：
文献类型：
--
作者：
Deng L;Bensing BA;Thamadilok S;Yu H;Lau K;Chen X;Ruhl S;Sullam PM;Varki A
受损的心脏瓣膜吸引血液传播的细菌，感染性心内膜炎通常是由草绿色链球菌引起的。虽然这些细菌使用多种粘附素来维持其正常的口腔黏膜状态，但血小板唾液酸聚糖的识别提供了与受损的瓣膜内皮细胞结合的中介。我们使用定制的唾液酸聚糖微阵列，以探索不同的结合特性的遗传相关的富含丝氨酸的重复粘附素，GspB，Hsa，和GSPA同源物从戈登链球菌和血链球菌物种，属于一个高度保守的家庭的糖蛋白，有助于广泛的革兰氏阳性病原体的毒力。含有新型唾液酸识别Siglec样结构域的重组可溶性同系物的结合谱与相应的全细菌与阵列的结合良好相关。这些细菌在体外显示出与合成的糖缀合物和分离的糖蛋白的聚糖、蛋白质或二价阳离子依赖性结合的多种模式。然而，已知内源性去唾液酸聚糖识别清除受体确保仅完全唾液酸化的聚糖在血管内系统中占主导地位，其中我们发现这些特定的链球菌变得主要依赖于其Siglec样粘附素用于聚糖介导的识别事件。值得注意的是，尽管在细胞和可溶性血液组分中存在过量的替代唾液酸聚糖配体，但这些粘附素选择性地将完整细菌靶向人全血中血小板上的唾液酸化配体。这些优选的相互作用被相应的重组可溶性粘附素抑制，其也优先识别血小板。我们的数据表明，循环中的血小板可能会作为口腔链球菌的特洛伊木马载体无意中到达受损的心内膜，并提供了一个解释，为什么在无数偶尔进入血液的微生物中，某些草绿色链球菌在受损的心脏瓣膜中具有选择性优势，并导致感染性心内膜炎。细菌感染性心内膜炎仍然是一种发病率和死亡率相当高的疾病。在众多可以进入血液的细菌中，某些口腔草绿色链球菌是心内膜炎的主要病原体。然而，这种选择性的机制尚未完全理解。这种细菌的粘附素和人血小板唾液酸聚糖之间的相互作用被认为在这种选择性中发挥重要作用，通过促进细菌粘附到受损的心脏瓣膜。然而，这些相互作用的分子要求没有充分探讨。特别是，目前还不清楚这些细菌对血小板的选择性靶向是否真的发生在流体人全血中，这是一种存在许多潜在唾液酸聚糖竞争者的环境。在目前的工作中，我们讨论了这些重要问题。我们详细描述了一系列富含丝氨酸的口腔链球菌重复粘附素的聚糖结合谱。我们首次证明口服链球菌确实可以选择性地靶向人全血中的血小板。作为一个概念的证明，我们还表明，可溶性重组细菌粘附素结合区蛋白可以阻止首选的血小板-细菌在全血中的相互作用。从这项研究中获得的知识可能有助于开发新的预防或治疗感染性心内膜炎的方法。
Damaged cardiac valves attract blood-borne bacteria, and infective endocarditis is often caused by viridans group streptococci. While such bacteria use multiple adhesins to maintain their normal oral commensal state, recognition of platelet sialoglycans provides an intermediary for binding to damaged valvular endocardium. We use a customized sialoglycan microarray to explore the varied binding properties of phylogenetically related serine-rich repeat adhesins, the GspB, Hsa, and SrpA homologs from Streptococcus gordonii and Streptococcus sanguinis species, which belong to a highly conserved family of glycoproteins that contribute to virulence for a broad range of Gram-positive pathogens. Binding profiles of recombinant soluble homologs containing novel sialic acid-recognizing Siglec-like domains correlate well with binding of corresponding whole bacteria to arrays. These bacteria show multiple modes of glycan, protein, or divalent cation-dependent binding to synthetic glycoconjugates and isolated glycoproteins in vitro. However, endogenous asialoglycan-recognizing clearance receptors are known to ensure that only fully sialylated glycans dominate in the endovascular system, wherein we find these particular streptococci become primarily dependent on their Siglec-like adhesins for glycan-mediated recognition events. Remarkably, despite an excess of alternate sialoglycan ligands in cellular and soluble blood components, these adhesins selectively target intact bacteria to sialylated ligands on platelets, within human whole blood. These preferred interactions are inhibited by corresponding recombinant soluble adhesins, which also preferentially recognize platelets. Our data indicate that circulating platelets may act as inadvertent Trojan horse carriers of oral streptococci to the site of damaged endocardium, and provide an explanation why it is that among innumerable microbes that gain occasional access to the bloodstream, certain viridans group streptococci have a selective advantage in colonizing damaged cardiac valves and cause infective endocarditis. Bacterial infective endocarditis remains a disease with considerable morbidity and mortality. Of the numerous bacteria that can enter the bloodstream, certain oral commensal viridans group streptococci are among the major causative organisms of endocarditis. However, mechanisms underlying this selectivity are incompletely understood. Interactions between adhesins of such bacteria and human platelet sialoglycans are believed to play an important role in this selectivity, by facilitating bacterial adherence to damaged heart valves. Nevertheless, the molecular requirements for these interactions are not fully explored. Particularly, it is unclear whether selective targeting of platelets by these bacteria actually occurs in fluid human whole blood, an environment where numerous potential sialoglycan competitors exist. In the present work, we have addressed these important issues. We characterize in detail the glycan-binding spectra of a series of serine-rich repeat adhesins of oral streptococci. For the first time, we demonstrate that oral streptococci can indeed selectively target platelets in whole human blood. As a proof of concept, we also show that soluble recombinant bacterial adhesin binding region proteins can block the preferred platelet-bacterial interactions in whole blood. The knowledge gained from this study may help the development of novel preventive or therapeutic approaches against infective endocarditis.
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影响因子：
3.1
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