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Impact of ß-glucan metabolism on the development of pathogenic biofilms

α-葡聚糖代谢对致病性生物膜形成的影响

基本信息

批准号：
10187549
负责人：
Kiyonobu Homma
金额：
$ 15.95万
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：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10187549
关键词：
Advanced Glycosylation End Products Affect Alveolar Bone Loss Applications Grants Bacteria Biomass Candida Carbon Cells Chronic Communication Communities Complex Data Dental Plaque Development Disease Enzymes Forsythia Foundations Fusobacterium nucleatum Future Genetic Transcription Glucans Glucose Goals Gram-Negative Bacteria Growth Human Hydrolase Hydrolysis In Vitro Inflammation Inflammatory Investigation Mediating Metabolic Metabolism Microbial Biofilms Modeling Molecular Mus Nutrient Odontogenesis Operon Oral Pathogenesis Pathogenicity Periodontal Infection Periodontitis Physiology Play Poison Production Publications Pyruvaldehyde Regulation Role Sigma Factor Source Specificity Stimulus Structure System Tissues Tooth Loss Tooth structure Virulence Yeasts alveolar bone beta-Glucans dental biofilm dietary dysbiosis in vitro Model inhibitor/antagonist member microbial microbial community mouse model oral bacteria oral microbial community pathogen polymicrobial biofilm response subgingival biofilm therapy development transcriptomics

项目摘要

Project Summary/Abstract Periodontitis is a bacterially induced chronic inflammation of the tooth supporting tissues that may result in alveolar bone destruction and tooth loss. Tannerella forsythia (Tf), a member of the ‘red-complex’ bacteria group, is one of the major pathogens implicated in periodontitis. T. forsythia has been shown to co-aggregate with the ‘bridge-bacterium’ Fusobacterium nucleatum (Fn) to form synergistic co-biofilms in vitro and induce alveolar bone loss in mice when co- infected with Fn. The overall goal of this proposal is to determine the molecular mechanisms of T. forsythia -F. nucleatum intergeneric interactions to better understand the pathogenesis of periodontitis. Our preliminary data show that a Tf secreted ß-glucanase enzyme (GlcA) whose expression is induced in response to Fn sensing plays a significant role in the development of mixed biofilms. We showed that this enzyme hydrolyzes ß-glucans into glucose, which serves as a nutrient for Fn to promote its biomass in Tf -Fn co-biofilms. Our data showed that the increased glucose availability did not affect Tf biomass but it rather enhanced the production of methylglyoxal (MGO), a highly reactive dicabonyl compound toxic to bacterial and host cells. The goal of this proposal is to understand the mechanistic basis of Tf-Fn interactions and how metabolic interactions between these two species contribute to the development of the dental plaque, dysbiosis and inflammation. Our working hypothesis is that b-glucanase produced by Tf in response to Fn, and possible other stimuli, releases glucose from dietary b- glucans as a nutrient for the microbial community at large and as a metabolic precursor for MGO secretion to favor microbial dysbiosis. To interrogate this hypothesis, we propose two specific aims: Aim 1: To define the molecular mechanism of regulation of Tf GlcA operon in response to Fn sensing. We will analyze the mechanism and function of ECF sigma-anti sigma system that is predicted to drive Tf glcA ß-glucanase operon to respond stimulate with Fn and other stimuli, and; Aim 2 To determine the mechanisms by which Fn resists Tf-produced methylglyoxal and how hydrolyzed glucans impact microbial community structure. Here, we will determine the molecular mechanisms by which Fn detoxifies MGO produced by Tf in biofilms and promote dental plaque development. Successful completion of this study will form the foundation for future investigations exploring the unique ability of Tf glucanase-MGO axis in promoting microbial dysbiosis and subsequently develop glucanase targeting inhibitors to block the synergistic Tf-Fn associations and dental plaque development for the treatment of periodontitis.

项目总结/摘要牙周炎是由细菌引起的牙齿支持组织的慢性炎症这可能导致牙槽骨破坏和牙齿脱落。Tannerella pasthia（Tf），a member 是牙周炎的主要致病菌之一。T. 已经证明，该菌与“桥细菌”具核梭杆菌共聚集 (Fn)在体外形成协同的共生物膜，并在小鼠中诱导牙槽骨丢失，感染Fn。本提案的总体目标是确定 T. P.核质属间相互作用，以更好地了解发病机制，牙周炎我们的初步数据表明，Tf分泌的β-葡聚糖酶（GlcA）， Fn传感诱导表达在混合型细胞的发展中起着重要作用。生物膜我们发现，这种酶水解β-葡聚糖为葡萄糖，葡萄糖作为Fn的营养物质，以促进其在Tf -Fn共生物膜中的生物量。我们的数据表明，葡萄糖可用性的增加并没有影响Tf生物量，但它反而增强了甲基乙二醛（MGO）的生产，对细菌和宿主细胞有毒的化合物。本提案的目的是了解Tf-Fn相互作用的机制基础以及这两个物种之间的代谢相互作用如何影响牙菌斑的发展、生态失调和炎症。我们的假设是由Tf响应于Fn和可能的其它刺激而产生的β-葡聚糖酶从膳食B-β-葡聚糖酶释放葡萄糖。葡聚糖作为微生物群落的营养素和作为MGO分泌的代谢前体有利于微生物的生态失调。为了质疑这一假设，我们提出了两个具体目标：目标1：阐明转铁蛋白GlcA操纵子对纤维连接蛋白感应的调控机制。我们将分析预测的ECF sigma-anti sigma系统的机制和功能驱动Tf glcA β-葡聚糖酶操纵子响应Fn等刺激物的刺激;目的2 为了确定Fn抵抗Tf产生的丙酮醛的机制，以及Fn如何抵抗Tf产生的丙酮醛，水解的葡聚糖影响微生物群落结构。在这里，我们将确定分子 Fn解毒生物膜中Tf产生的MGO并促进牙菌斑的机制发展本研究的成功完成将为未来的调查研究奠定基础。 Tf葡聚糖酶-MGO轴在促进微生物生态失调和随后发育中独特能力葡聚糖酶靶向抑制剂阻断协同的Tf-Fn缔合和牙菌斑牙周炎的治疗。