Abstract

Streptococcus gordonii and Streptococcus sanguinis are primary colonizers of tooth surfaces and are generally associated with oral health, but can also cause infective endocarditis (IE). These species express “Siglec-like” adhesins that bind sialylated glycans on host glycoproteins, which can aid the formation of infected platelet–fibrin thrombi (vegetations) on cardiac valve surfaces. We previously determined that the ability of S. gordonii to bind sialyl T-antigen (sTa) increased pathogenicity, relative to recognition of sialylated core 2 O-glycan structures, in an animal model of IE. However, it is unclear when and where the sTa structure is displayed, and which sTa-modified host factors promote valve colonization. In this study, we identified sialylated glycoproteins in the aortic valve vegetations and plasma of rat and rabbit models of this disease. Glycoproteins that display sTa vs. core 2 O-glycan structures were identified by using recombinant forms of the streptococcal Siglec-like adhesins for lectin blotting and affinity capture, and the O-linked glycans were profiled by mass spectrometry. Proteoglycan 4 (PRG4), also known as lubricin, was a major carrier of sTa in the infected vegetations. Moreover, plasma PRG4 levels were significantly higher in animals with damaged or infected valves, as compared with healthy animals. The combined results demonstrate that, in addition to platelet GPIbα, PRG4 is a highly sialylated mucin-like glycoprotein found in aortic valve vegetations and may contribute to the persistence of oral streptococci in this protected endovascular niche. Moreover, plasma PRG4 could serve as a biomarker for endocardial injury and infection.

中文翻译：

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蛋白多糖 4（润滑素）是一种高度唾液酸化的糖蛋白，与感染性心内膜炎动物模型中的心脏瓣膜损伤相关

摘要

戈登链球菌和血链球菌是牙齿表面的主要定植菌，通常与口腔健康有关，但也可引起感染性心内膜炎 (IE)。这些物种表达“Siglec 样”粘附素，可结合宿主糖蛋白上的唾液酸化聚糖，这有助于在心脏瓣膜表面形成受感染的血小板-纤维蛋白血栓（植物）。我们之前确定S. gordonii结合唾液酸 T 抗原 (sTa) 的能力增加了致病性，相对于唾液酸化核心 2 O的识别-聚糖结构，在IE的动物模型中。然而，尚不清楚何时何地显示 sTa 结构，以及哪些 sTa 修饰的宿主因子促进瓣膜定植。在这项研究中，我们在这种疾病的大鼠和兔模型的主动脉瓣赘生物和血浆中鉴定了唾液酸化糖蛋白。通过使用重组形式的链球菌 Siglec 样粘附素进行凝集素印迹和亲和捕获，鉴定了显示 sTa 与核心 2 O-聚糖结构的糖蛋白，以及O通过质谱分析连接的聚糖。蛋白多糖 4 (PRG4)，也称为润滑素，是受感染植被中 sTa 的主要载体。此外，与健康动物相比，瓣膜受损或感染动物的血浆 PRG4 水平显着升高。综合结果表明，除了血小板 GPIbα 外，PRG4 是一种在主动脉瓣赘生物中发现的高度唾液酸化的粘蛋白样糖蛋白，可能有助于口腔链球菌在这个受保护的血管内生态位中持续存在。此外，血浆 PRG4 可作为心内膜损伤和感染的生物标志物。