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：
10520050
负责人：
Ashu Sharma
金额：
$ 35.4万
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/10520050
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 Invaded Knowledge Ligands 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 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 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 pharmacologic prevent response salivary mucins sialate sialylation subgingival microbiota synergism targeted treatment therapeutic evaluation

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，一种导致牙齿退化的炎症性疾病支撑结构通常会导致牙齿脱落，并且是许多全身性疾病的危险因素，影响着 700 多人全球 100 万人，估计每年的经济负担总计 4,420 亿美元。细菌三联体被称为“红色复合体”，由牙龈卟啉单胞菌、齿垢密螺旋体和坦纳菌组成连翘与该疾病的发病机制密切相关。但尚不清楚为什么这三种病原体对牙周炎的发展影响很大。虽然这些细菌会产生促进其定植、破坏宿主免疫力和促进龈下多种微生物生长的因素有很多协同作用和生态失调，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、免疫细胞和唾液中的糖蛋白中裂解末端唾液酸牙龈沟的分泌物。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释放唾液酸来发病机制作为营养物质以及表面唾液酸化和合成重要细菌成分的前体，例如肽聚糖（细菌细胞壁）。在此应用中，我们将重点关注连翘唾液酸酶 NanH 作为对连翘（一种有机体）的生存具有独特贡献的原型病原体酶肽聚糖结构单元氨基糖 N-乙酰胞壁酸 (MurNAc) 营养缺陷。南海唾液酸酶活性可以促进早期细菌-上皮细胞相互作用，导致先天免疫破坏响应并提供生物膜中 MurNAc 生物合成的方法，并可能改善细菌的通过减少对共居细菌提供 MurNAc 和的依赖，在龈下生态位中生存肽聚糖片段。我们的假设是，T. 的唾液酸和肽聚糖的觅食活动。连翘通过促进细菌定植、生物膜适应性和宿主而加剧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唾液酸的影响肽聚糖清除和发病机制，以及 3) 确定微生物唾液酸酶的贡献在多种微生物生态和炎症的调节中，同时还研究了抗微生物的潜力唾液酸酶药物，例如 FDA 批准的药物 TamiFlu（奥司他韦）可预防小鼠牙周炎模型。该提案将采取深入的方法来定义宿主唾液酸糖组病原体的影响从宿主和微生物的角度来看，相互作用。它还将重点关注新的唾液酸肽聚糖轴连翘并定义该轴对于连翘适应性的重要性。此外，作为原则证明，它将在小鼠模型中测试药理学唾液酸酶抑制剂缓解牙周病的治疗潜力炎症并重塑生态失调，使其恢复健康并改善牙周炎疾病的结果。