Microbial Recognition of Sialic Acid Diversity in the Oral Cavity

口腔中唾液酸多样性的微生物识别

• 批准号: 10192699
• 负责人: Stefan Hans-Klaus Ruhl
• 金额: $ 50.48万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192699
• 关键词: Adhesions; Bacteria; Bacterial Adhesins; Bacterial Adhesion; Binding; Biological Assay; Blood Circulation; Carbon; Cell Line; Cell surface; Cells; Clinical; Dental Plaque; Dental caries; Disease; Early Diagnosis; Endocarditis; Enzymes; Event; Family; Far-Western Blotting; Flow Cytometry; Fluorescence Microscopy; Future; Gene Mutation; Gene Silencing; Genomics; Gingiva; Glycolipids; Glycoproteins; Gorilla gorilla; Heterophile Antigens; Host Defense; Human; Immune response; Individual; Infection; Knowledge; Laboratories; Lead; Lipids; Mammals; Measurement; Mediating; Microbe; Microbial Biofilms; Modification; Molecular; Mouth Diseases; N-Acetylneuraminic Acid; N-glycolylneuraminic acid; Oral; Oral cavity; Outcome; Oxygen; Pan Genus; Pathogenicity; Pathologic Processes; Periodontal Diseases; Phagocytes; Phagocytosis; Pharmacology; Physiological Processes; Play; Polysaccharides; Pongidae; Positioning Attribute; Prevention; Process; Proteins; Proteomics; Recombinant DNA; Risk; Role; Saliva; Salivary; Salivary Proteins; Serine; Sialic Acids; Sialoglycoproteins; Source; Specificity; Streptococcus; Streptococcus adhesin; Structure; Sugar Acids; Surface; Suspensions; Systemic disease; Testing; Tissues; Tooth Diseases; Tropism; Variant; Virus; base; commensal bacteria; dietary; granulocyte; host colonization; host-microbe interactions; improved; microbial; microorganism; neutrophil; novel; oral biofilm; oral commensal; oral microbiome; oral streptococci; prevent; receptor; risk prediction; screening; three dimensional structure; uptake

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.

项目摘要 唾液酸（SIAS），装饰糖蛋白和糖脂的聚糖链的最外部末端， 包括一个多元化的九种碳糖酸的家族，其中结构变体由 在不同的碳位置取代。 SIA参与细胞细胞识别过程和 调节多种生理和病理过程，包括病毒识别 和其他致病微生物。在唾液糖蛋白上，终末SIA构成重要 通过口服共生链球菌的SIA结合粘合剂识别的同源性聚糖基序。这 识别可以通过链球菌对唾液涂层的口腔表面进行初始粘附和定植。 但是，如果这些通常是无害的共生SIA结合链球菌，则碰巧 牙龈边缘的组织屏障和逃避中性粒细胞防御，它们可以分散 血液和充当全身性疾病的药物，包括感染性心内膜炎。因为 SIA在所有这些事件中都起作用 SIAS的亚型成为要探索的重要问题。我们的小组最近表演了 全面筛查牙菌斑链球菌菌株的临床分离株的能力 与不同的SIA亚型结合。通过使用A分析其较细的SIA-SUBTYPE结合特异性 新型的唾液酸阵列，我们在人类的口腔中发现与一个人的口腔链球菌 非人类唾液酸，n-糖基因神经氨酸（NEU5GC）。这很重要，因为人类， 与大多数其他哺乳动物不同，在遗传上无法合成NEU5GC。在这个项目中，我们的目标是 通过这些SIA结合确定对NEU5GC和NEU5AC差异识别的结构基础 链球菌，并在人口腔中鉴定其天然受体。我们将调查 SIA介导的链球菌与唾液唾液糖蛋白的结合的分子基础。我们将确定 口服生物膜中的其他细菌物种在其表面表达SIA，并且是 Neu5GC结合链球菌的细菌粘附。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 链球菌与细菌摄取和吞噬细胞激活的不同SIA辅助类型的结合。全面的， 预计这些研究将通过证明SIA-SUBTYPES的表达来揭开新的基础 影响人口腔中的细菌宿主相互作用。获得的知识可能会有 对早期诊断和预防牙齿，口腔和全身性疾病的积极影响 口服微生物。