Microbial Recognition of Sialic Acid Diversity in the Oral Cavity

项目摘要 唾液酸（Sias），修饰糖蛋白和糖脂的聚糖链的最外末端， 包括不同的九碳糖酸家族，其中结构变体定义为 在不同的碳位置取代。Sias参与细胞-细胞识别过程， 调节多种生理和病理过程，包括病毒识别 和其他病原微生物。在唾液糖蛋白中，末端Sias构成重要的 由口腔链球菌的Sia结合粘附素识别的同源聚糖基序。这 识别使得链球菌能够初始粘附并定殖唾液包被的口腔表面。 然而，如果这些通常无害的唾液酸结合链球菌碰巧违反了 组织屏障在牙龈边缘和逃避中性粒细胞防御，他们可以成为分散内 血液循环和作为系统性疾病，包括感染性心内膜炎的代理人。因为 Sias在所有这些事件中发挥作用，链球菌结合各种 Sias亚型成为一个值得探讨的重要问题。我们小组最近表演了一个 牙菌斑链球菌菌株临床分离株的综合筛选， 与不同的Sia亚型结合通过分析其更精细的Sia亚型结合特异性， 我们在人类个体的口腔中发现了链球菌， 非人唾液酸，N-羟乙酰神经氨酸（Neu 5Gc）。这很重要，因为人类， 与大多数其他哺乳动物不同，它们在遗传上不能合成Neu 5Gc。在这个项目中，我们的目标是 通过这些Sia结合确定Neu 5Gc和Neu 5Ac的差异识别的结构基础 链球菌，并确定其在人类口腔中的天然受体。我们将调查 Sia介导的链球菌与唾液唾液酸糖蛋白结合的分子基础。我们将确定 口腔生物膜中的其他细菌物种在其表面上表达Sias，并且是 Neu 5Gc结合链球菌的细菌间粘附。最后，我们将确定分子基础 Sia介导的链球菌与吞噬细胞的结合，并研究 链球菌与不同Sia亚型的结合对细菌摄取和吞噬细胞活化的影响。总体而言， 这些研究有望通过证明Sia亚型的表达 影响人类口腔中的细菌-宿主相互作用。获得的知识可能会 对牙齿、口腔和全身性疾病的早期诊断和预防产生积极影响， 口腔微生物

PROJECT SUMMARY Sialic acids (Sias), the outermost termini of glycan chains decorating glycoproteins and glycolipids, comprise a diverse family of nine-carbon sugar acids, where structural variants are defined by substitutions at different carbon positions. Sias are involved in cell-cell recognition processes and modulate a wide variety of physiological and pathological processes, including recognition by viruses and other pathogenic microorganisms. On salivary glycoproteins, terminal Sias constitute important cognate glycan motifs recognized by Sia-binding adhesins of oral commensal streptococci. This recognition enables initial adhesion and colonization of saliva-coated oral surfaces by streptococci. However, if these normally harmless commensal Sia-binding streptococci happen to transgress the tissue barrier at the gingival margin and evade neutrophil defense, they can become dispersed within the bloodstream and act as agents of systemic diseases, including infectious endocarditis. Because Sias play a role in all of these events, the finer specificities of streptococcal binding to the various subtypes of Sias become an important question to explore. Our group has recently performed a comprehensive screening of clinical isolates of dental plaque streptococcal strains for their ability to bind to different Sia subtypes. Through analyzing their finer Sia-subtype binding specificities using a novel sialoglycan array, we found streptococci in the oral cavity of human individuals that bind to a non-human sialic acid, N-glycolylneuraminic acid (Neu5Gc). This is significant because humans, unlike most other mammals, are genetically unable to synthesize Neu5Gc. In this project, we aim to determine the structural basis for differential recognition of Neu5Gc and Neu5Ac by these Sia-binding streptococci, and to identify their natural receptors in the human oral cavity. We will investigate the molecular basis of Sia-mediated streptococcal binding to salivary sialoglycoproteins. We will identify other bacterial species in oral biofilms that express Sias on their surface and are targets for interbacterial adhesion by Neu5Gc-binding streptococci. Lastly, we will determine the molecular basis of Sia-mediated binding of streptococci to phagocytes and investigate the functional consequences of streptococcal binding to different Sia-subtypes on bacterial uptake and phagocyte activation. Overall, these studies are expected to break new ground by demonstrating how expression of Sia-subtypes influences bacteria-host interactions in the human oral cavity. The knowledge gained will likely have a positive impact on early diagnosis and prevention of dental, oral, and systemic diseases caused by oral microbes.