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

• 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
• 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

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.

项目概要/摘要。牙周炎，一种导致牙齿退化的炎症性疾病 支撑结构往往导致牙齿脱落，是许多系统性疾病的危险因素，影响超过700 全球有100万人，估计每年的经济负担总计4，420亿美元。细菌三联体 称为"红色复合物"，由牙龈卟啉单胞菌、齿垢密螺旋体和坦纳氏菌组成 该疾病的发病机制与乳腺癌密切相关。然而，人们并不清楚为什么 这三种病原体在牙周炎的发展中影响很大。当这些细菌产生一种 许多因素促进其定植，破坏宿主免疫力，促进龈下多微生物 有趣的是，这三种病原体都产生唾液酸酶（神经氨酸酶）--一种可以 从上皮细胞、免疫细胞表面和唾液中的糖蛋白上切割末端唾液酸， 龈沟分泌物。我们假设这些病原体的唾液酸酶活性在 通过先天免疫因子的结构-功能活性的破坏和唾液酸的释放的发病机制 作为营养物以及表面唾液酸化和合成重要细菌组分的前体， 肽聚糖（细菌细胞壁）。在这个应用程序中，我们将重点放在T。唾液酸酶NanH作为 在T.一种有机体 肽聚糖结构单元氨基糖N-乙酰胞壁酸（MurNAc）的营养缺陷型。关于NANH 唾液酸酶活性可促进早期细菌-上皮细胞相互作用，导致先天免疫破坏， 反应，并提供生物膜中MurNAc生物合成的手段，并可能改善细菌的 通过减少其对共存细菌的依赖来提供MurNAc， 肽聚糖片段。我们假设T. 通过促进细菌定植，生物膜适应性和宿主， 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 2）定义唾液酸的代谢命运和唾液酸利用对唾液酸代谢的影响。 肽聚糖清除和发病机理，和3）确定微生物唾液酸酶的贡献 在调节多微生物生态学和炎症的同时，还研究了抗- 唾液酸酶药物如FDA批准的药物TamiFlu（奥司他韦）在小鼠中阻断牙周炎 模型该建议将采取深入的方法来确定宿主唾液酸酶-病原体的影响 从宿主和微生物的角度来看。它还将集中在一个新的唾液酸肽聚糖轴， t.并定义这个轴对T的重要性。连翘健身。此外，作为原则的证明，它将 测试药理学唾液酸酶抑制剂在小鼠模型中缓解牙周炎的治疗潜力， 炎症和重塑生态失调恢复健康和改善牙周炎疾病的结果。