L-Arg availability affects the physiological state of porphyromonas gingivalis.

L-精氨酸的可用性影响牙龈卟啉单胞菌的生理状态。

基本信息

批准号：
10649693
负责人：
Mary Ellen Davey
金额：
$ 40.92万
依托单位：
ADA FORSYTH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649693
关键词：
Adult Affect Affinity Agar Alzheimer&apos s Disease Amino Acids Anabolism Anaerobic Bacteria Arginine Arginine deiminase Bacteria Biochemical Biogenesis Biological Assay Carboxypeptidase Cardiovascular Diseases Caspase Cells ChIP-seq Clinical Communities Complex Cues Data Development Disease Disease Progression Epithelium Equilibrium Excision Genes Germ-Free Gingival Crevicular Fluid Goals Growth Homeostasis Human Hydration status Image Immune response Indigenous Infection Inflammatory Knowledge Laboratories Larva Life Life Style Link Lipoproteins Mediating Membrane Metabolism Methods Microbial Biofilms Modeling Molecular Monitor Moths Movement Mus Nutritional Oral cavity Pathogenicity Pathology Peptide Hydrolases Peptides Periodontal Diseases Periodontal Infection Periodontitis Phenotype Physiological Physiology Pilum Polyamines Population Porphyromonas gingivalis Prevention Proliferating Protocols documentation Regulation Regulon Reporting Research Rheumatoid Arthritis Signal Transduction Slide Surface Surface Tension System Systemic disease Testing Time United States Urocanate Hydratase Vesicle Virulence Waxes appendage cell motility chronic inflammatory disease cost differential expression dysbiosis extracellular genetic regulatory protein gingipain host microbiome host-associated microbial communities immunoregulation inflammatory bone loss metabolomics microbial community microbiome microbiota migration mutant oral anaerobes oral microbiome oral pathogen palmitoylation pathogen pathogenic bacteria programs response sensor subgingival biofilm targeted treatment therapeutic development transcriptome sequencing transcriptomics transmission process uptake

项目摘要

Project Summary/Abstract Many chronic inflammatory diseases, including periodontal infections, are biofilm-based pathologies mediated by indigenous microbiota persisting within complex host-associated microbial communities. Determining the environmental cues that direct the physiological state (commensal versus pathogenic state) of oral anaerobes, is fundamental to development of therapeutic strategies for periodontal diseases. Recent studies indicate that the pathogenic potential of the anaerobic bacterium Porphyromonas gingivalis is not solely dependent on its ability to colonize and proliferate within the subgingival biofilm; its physiological state and its associations within the microbial consortium are fundamental to development of pathology. The central hypothesis for this application is that the availability of L-arginine is a key signal/substrate that impacts P. gingivalis surface translocation, expression of virulence determinants, and biofilm formation. Studies have reported that the levels of arginine increase 2-fold (from ~5µM to 10µM) in gingival crevicular fluid during periodontal disease. The reason for this increase is not known but may reflect a decrease in metabolism by the microbial community, a decrease in uptake by host cells, or an increase in bacterial arginine biosynthesis. One known factor is the activity of the arginine - specific cysteine proteases (Arg-gingipains) produced by P. gingivalis, along with its carboxypeptidase that releases the terminal arginine residues from peptides produced by Arg- gingipains. Our analysis shows that both intracellular and extracellular accumulation of L-arginine has a negative impact on P. gingivalis physiology, confirming that the levels of L-arginine are monitored and controlled. Our studies have shown that under L-arginine deplete conditions, P. gingivalis down regulates expression of fimbriae, inhibiting biofilm formation; and, in contrast, addition of L-arginine boosts fimbrial expression and surface colonization. Thus, P. gingivalis adjusts its lifestyle in response to changes in extracellular L-arginine. What remains unclear is the sensing and regulatory mechanisms that control this change in physiology. The goal of this application is to determine how P. gingivalis controls extracellular and intracellular arginine concentrations and in particular the effect of changes in arginine concentration on its ability to surface translocate. Importantly, L-arginine is known to be an important modulator of the host immune response to pathogens, so we posit that there is a delicate balance between host and pathogen responses to arginine during disease progression and that P. gingivalis has evolved with the ability to sense and respond to this key amino acid as a fundamental strategy for persistence. The rationale for these studies is that identifying the signals that control colonization and the physiological state of oral pathogens will provide prime targets for the development of therapeutic strategies. Thus, the long-term objective is to determine if this mechanism of signaling can be targeted for treatment and prevention of biofilm-induced diseases in humans.

项目概要/摘要许多慢性炎症性疾病，包括牙周感染，都是由生物膜介导的病理学通过在复杂的宿主相关微生物群落中持续存在的本土微生物群来确定。指导口腔厌氧菌生理状态（共生状态与致病状态）的环境线索，最近的研究表明，这是制定牙周病治疗策略的基础。厌氧菌牙龈卟啉单胞菌的致病潜力并不仅仅取决于其在龈下生物膜内定植和增殖的能力及其生理状态及其内部的关联；微生物群落是病理学发展的基础，这是其核心假设。应用表明，L-精氨酸的可用性是影响牙龈卟啉单胞菌表面的关键信号/底物研究报告称，易位、毒力决定子的表达和生物膜形成。牙周病期间，龈沟液中的精氨酸水平增加了 2 倍（从约 5μM 至 10μM）。这种增加的原因尚不清楚，但可能反映了微生物代谢的减少一种已知的现象是，宿主细胞的摄取减少，或细菌精氨酸生物合成增加。因子是由牙龈卟啉单胞菌产生的精氨酸-特异性半胱氨酸蛋白酶（Arg-gingipains）的活性，连同它的羧肽酶一起从 Arg- 产生的肽中释放末端精氨酸残基我们的分析表明，L-精氨酸在细胞内和细胞外的积累都有一定的影响。对牙龈卟啉单胞菌生理学的负面影响，证实 L-精氨酸的水平受到监测并我们的研究表明，在 L-精氨酸耗尽的条件下，牙龈卟啉单胞菌下调。菌毛的表达，抑制生物膜的形成；相反，添加 L-精氨酸可以促进菌毛的形成；因此，牙龈卟啉单胞菌会根据变化来调整其生活方式。目前尚不清楚的是控制这种现象的传感和调节机制。该应用的目的是确定牙龈卟啉单胞菌如何控制细胞外和细胞内精氨酸浓度，特别是精氨酸浓度变化对其的影响重要的是，L-精氨酸是宿主免疫的重要调节剂。对病原体的反应，因此我们假设宿主和病原体对病原体的反应之间存在微妙的平衡疾病进展期间的精氨酸，并且牙龈卟啉单胞菌已经进化出具有感知和响应的能力这种关键氨基酸作为持久性的基本策略是这些研究的基本原理是：识别控制口腔病原体定植和生理状态的信号将为因此，长期目标是确定这是否是制定治疗策略的目标。信号传导机制可用于治疗和预防人类生物膜引起的疾病。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Growth of Porphyromonas gingivalis on human serum albumin triggers programmed cell death.

DOI：
10.1080/20002297.2022.2161182
发表时间：
2023
期刊：
Journal of oral microbiology
影响因子：
4.5
作者：
通讯作者：

Characterization of a Bacterial Kinase That Phosphorylates Dihydrosphingosine to Form dhS1P.

DOI：
10.1128/spectrum.00002-22
发表时间：
2022-04-27
期刊：
Microbiology spectrum
影响因子：
3.7
作者：
通讯作者：

A Novel Regulation of K-antigen Capsule Synthesis in Porphyromonas gingivalis Is Driven by the Response Regulator PG0720-Directed Antisense RNA.

DOI：
10.3389/froh.2021.701659
发表时间：
2021
期刊：
Frontiers in oral health
影响因子：
0
作者：
Kim HM;Ranjit DK;Walker AR;Getachew H;Progulske-Fox A;Davey ME
通讯作者：
Davey ME

Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer.

DOI：
10.1038/s41598-017-17795-z
发表时间：
2017-12-15
期刊：
Scientific reports
影响因子：
4.6
作者：
Börnigen D;Ren B;Pickard R;Li J;Ozer E;Hartmann EM;Xiao W;Tickle T;Rider J;Gevers D;Franzosa EA;Davey ME;Gillison ML;Huttenhower C
通讯作者：
Huttenhower C

Sphingolipid-Containing Outer Membrane Vesicles Serve as a Delivery Vehicle To Limit Macrophage Immune Response to Porphyromonas gingivalis.