Bacterial sialometabolic activity impacts periodontal immunity and microbiota

细菌唾液酸代谢活动影响牙周免疫和微生物群

基本信息

批准号：
10310503
负责人：
Ashu Sharma
金额：
$ 35.05万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10310503
关键词：
Acetylesterase Acute Address Adult Affect Amino Sugars Anabolism Antibiotic Therapy Back Bacteria Bacterial Adhesion Biota CD14 gene Cell Communication Cell Wall Cells Complex Dependence Development Disease Disease Outcome Ecology Economic Burden Enzyme Inhibitor Drugs Enzymes Epithelial Cells Excision FDA approved Flagellin Forsythia Genome Gingiva Gingival Crevicular Fluid Glycoproteins Growth Health Human Immune Immune response Immunity Immunologic Factors Infection Inflammation Inflammatory Influentials Innate Immune Response Knowledge Lead Ligands Light Medical Metabolic Microbial Biofilms Microbiology Mining Molecular Mucin 1 protein Mus N-acetylmuramic acid Natural Immunity Nature Neuraminidase Nutrient Oral Organism Orthologous Gene Oseltamivir Pathogenesis Pathway interactions Patients Peptidoglycan Periodontal Diseases Periodontitis Periodontium Persons Pharmaceutical Preparations Pharmacology Physiology Play Polysaccharides Porphyromonas gingivalis Process Proteins Recombinants Regulation Resistance Risk Factors Role Saliva Salivary Serum Sialic Acids Sialoglycoproteins Signal Transduction Site Specificity Streptococcus oralis Structure Sugar Acids Surface System Systemic disease Testing Tissues Tooth Loss Tooth structure Topical application Treponema denticola Triad Acrylic Resin Virulence Work bacterial resistance cytokine dysbiosis fitness improved in vivo inhibitor inhibitor therapy insight microbial microbiota mouse model novel oral bacteria pathogen pathogenic bacteria periodontopathogen prevent response salivary mucins sialate sialylation subgingival microbiota synergism targeted treatment therapeutic evaluation

Acetylesterase Acute Address Adult Affect Amino Sugars Anabolism Antibiotic Therapy Back Bacteria Bacterial Adhesion Biota CD14 gene Cell Communication Cell Wall Cells Complex Dependence Development Disease Disease Outcome Ecology Economic Burden Enzyme Inhibitor Drugs Enzymes Epithelial Cells Excision FDA approved Flagellin Forsythia Genome Gingiva Gingival Crevicular Fluid Glycoproteins Growth Health Human Immune Immune response Immunity Immunologic Factors Infection Inflammation Inflammatory Influentials Innate Immune Response Knowledge Lead Ligands Light Medical Metabolic Microbial Biofilms Microbiology Mining Molecular Mucin 1 protein Mus N-acetylmuramic acid Natural Immunity Nature Neuraminidase Nutrient Oral Organism Orthologous Gene Oseltamivir Pathogenesis Pathway interactions Patients Peptidoglycan Periodontal Diseases Periodontitis Periodontium Persons Pharmaceutical Preparations Pharmacology Physiology Play Polysaccharides Porphyromonas gingivalis Process Proteins Recombinants Regulation Resistance Risk Factors Role Saliva Salivary Serum Sialic Acids Sialoglycoproteins Signal Transduction Site Specificity Streptococcus oralis Structure Sugar Acids Surface System Systemic disease Testing Tissues Tooth Loss Tooth structure Topical application Treponema denticola Triad Acrylic Resin Virulence Work bacterial resistance cytokine dysbiosis fitness improved in vivo inhibitor inhibitor therapy insight microbial microbiota mouse model novel oral bacteria pathogen pathogenic bacteria periodontopathogen prevent response salivary mucins sialate sialylation subgingival microbiota synergism targeted treatment therapeutic evaluation

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项目摘要

Project Summary/Abstract. Periodontitis, an inflammatory disease resulting in the degradation of the tooth supporting structures often leading to tooth loss, and a risk factor for many systemic diseases, affects over 700 million people worldwide with an estimated economic burden totaling $442 billion per year. A bacterial triad known as the `red-complex' comprising of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia is strongly implicated in the pathogenesis of the disease. However, it is not clearly understood why these three pathogens are so influential in the development of periodontitis. While these bacteria produce a number of factors to facilitate their colonization, undermine host immunity and promote subgingival polymicrobial synergy and dysbiosis, intriguingly, all three pathogens produce sialidase (neuraminidase) - an enzyme that can cleave terminal sialic acid from glycoproteins on the surface of epitheilial cells, immune cells and in salivary and gingival crevicular secretions. We hypotheisize that sialidase activity of these pathogens plays a critical role in the pathogenesis via disruption of structure-function activity of innate immune factors and liberation of sialic acid as a nutrient as well as a precursor for surface sialylation and synthesis of vital bacterial components such as peptidoglycan (bacterial cell-wall). In this application we will focus on the T. forsythia sialidase enzyme NanH as the prototypical pathogen enzyme with a unique contribution in the survival of T. forsythia - an organism auxotrophic for the peptidoglycan building block amino-sugar N-acetylmuramic acid (MurNAc). The NanH sialidase activity can promote early bacterial-epithelial cell interactions, cause disruption of innate immune responses and provide a means for the biosynthesis of MurNAc in biofilms and likely improves bacterium's survival in the subgingival niche by reducing its reliance on cohabiting bacteria to provide MurNAc and peptidoglycan fragments. Our hypothesis that sialic acid and peptidoglycan foraging activity of T. forsythia exacerbates periodontitis by promoting bacterial colonization, biofilm fitness, and host immune disruption will be addressed via: 1) Molecular level characterization of sialidase-host interactions, 2) Defining the metabolic fate of sialic acid and the impact of sialic acid utilization on peptidoglycan scavenging and pathogenesis, and 3) Determining the contribution of microbial sialidases in the modulation of polymicrobial ecology and inflammation while also examining the potential of anti- sialidase drugs such as FDA approved drugs TamiFlu (oseltamivir) in blocking periodontitis in a mouse model. This proposal will take an in-depth approach to define the influence of host sialoglycome-pathogen interactions from both the host and microbial standpoint. It will also focus on a novel sialo-peptidoglycan axis in T. forsythia and define how this axis might be critical for T. forsythia fitness. Further, as a proof of principle, it will test the therapeutic potential of pharmacological sialidase inhibitors in a mouse model to alleviate periodontal inflammation and remodel dysbiotic ecology back to health and improve periodontitis disease outcomes.

项目摘要/摘要。牙周炎，一种炎症性疾病，导致牙齿降解辅助结构通常导致牙齿脱落，而许多全身性疾病的危险因素会影响700多个全球有百万人民，估计每年的经济负担总计4420亿美元。细菌三合会被称为“红色复合物”，包括牙龈卟啉单胞菌，treponema denticola和tannerella 方际与该疾病的发病机理有很大的影响。但是，尚不清楚为什么这三种病原体对牙周炎的发展非常有影响力。这些细菌产生促进其定殖，破坏宿主免疫并促进亚生物多细胞的因素数量协同和营养不良，有趣的是，所有三种病原体都会产生唾液酸酶（神经氨酸酶） - 一种可以从上皮细胞，免疫细胞和唾液和唾液和牙龈刺激性分泌物。我们假设这些病原体的唾液酸酶活性在通过破坏先天免疫因子的结构功能活性和唾液酸解放的发病机理作为养分和前体，用于表面溶性和合成重要的细菌成分，例如肽聚糖（细菌细胞壁）。在此应用中，我们将重点介绍T. forsythia sialidase酶Nanh作为具有独特贡献的原型病原体酶在T. forsythia的存活中做出了独特的贡献 - 一种生物肽聚糖块氨基糖N-乙酰氨基甲酸（MURNAC）的营养营养不良。 Nanh 唾液酸酶活性可以促进早期细菌上皮细胞相互作用，导致先天免疫的破坏反应并为生物膜中Murnac的生物合成提供一种手段，并可能改善细菌的生物合成通过减少其对同居细菌的依赖，以提供Murnac和Murnac和肽聚糖碎片。我们的假设是唾液酸和肽聚糖的觅食活性。通过促进细菌定殖，生物膜适应性和宿主，加剧了牙周炎免疫破坏将通过以下方式解决：1）唾液酸酶宿主的分子水平表征相互作用，2）定义唾液酸的代谢命运以及唾液酸利用对肽聚糖清除和发病机理，以及3）确定微生物唾液酸酶的贡献在调节多数生态学和炎症时，同时还研究了抗 - 唾液酸酶药物，例如FDA批准的tamiflu（oseltamivir），用于阻断小鼠牙周炎模型。该提议将采用一种深入的方法来定义宿主唾液症状 - 疾病的影响从主机和微生物的角度进行相互作用。它还将重点放在一个新型的sialo-peptidoglycan轴上 T. Forsythia并定义该轴对T. Forsythia Fitness可能至关重要。此外，作为原则的证明，它将在小鼠模型中测试药理学唾液酸酶抑制剂的治疗潜力以减轻牙周炎症和重塑失调生态学回到健康并改善牙周炎疾病结局。