L-Arg Availability Affects the Physiological State of Porphyromonas gingivalis

L-精氨酸可用性影响牙龈卟啉单胞菌的生理状态

基本信息

批准号：
8886720
负责人：
Mary Ellen Davey
金额：
$ 37.5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886720
关键词：
Adherence Adult Affect Amino Acids Anaerobic Bacteria Arginine Arginine deiminase Bacteria Cardiovascular Diseases Catabolism Cells ChIP-seq Chromosomes Chronic Communities Complex Cues Data Development Diabetes Mellitus Disease Disease Progression Enzyme-Linked Immunosorbent Assay Epithelial Cells Epithelium Excision Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Screening Germ-Free Gingiva Goals Growth Human IL6 gene IL8 gene Image Immune In Vitro Infection Inflammatory Interleukin-1 beta Lead Libraries Life Style Mediating Mediator of activation protein Metabolism Microbial Biofilms Microscopy Molecular Mus Mutation Oral Oral cavity Organism Pathogenicity Pathology Periodontal Diseases Periodontal Infection Periodontitis Physiological Physiology Population Porphyromonas gingivalis Prevention Prokaryotic Cells Proliferating Regulation Research Resources Scientist Signal Transduction Site Streptococcus cristatus Stroke Structure Surface System Systemic disease Time United States Virulence Work base benign state bone loss clinically relevant commensal microbes cost experience fimbria genetic regulatory protein keratinocyte macrophage microbial microbial community monocyte mouse model mutant oral anaerobes oral commensal oral pathogen oral streptococci pathogen primitive cell promoter public health relevance response skills subgingival biofilm targeted treatment therapeutic development transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Many chronic inflammatory diseases, including periodontal infections, are biofilm-based pathologies mediated by commensal 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 P. gingivalis is not solely dependent on its ability to colonize and proliferate; its physiological stte and its associations within the microbial consortium are fundamental to development of pathology. The central hypothesis for the studies proposed here is that the availability of L-arginine is a key signal that directs colonization and expression of virulence determinants in P. gingivalis. Our preliminary 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 expression of fimbriae and surface colonization. Thus, P. gingivalis adjusts its life style in response to changes in the availability of L-arginine. Moreover, this adjustment has a subsequent impact on its interactions with other bacteria and host cells. What remains unclear is why L-arginine is such an important amino acid to P. gingivalis and how changes in L-arginine availability affect its physiology. The goal of this application is to determine how P. gingivalis senses arginine availability and how it responds to this particular amino acid and to determine the effect of arginine on its interaction with human macrophages and oral epithelial cells. We posit that arginine is a critical resource that is crucial for immune regulation and P. gingivalis has evolved with the ability to sense and respond to this key amino acid, not just as a growth substrate, but 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.

描述（由申请人提供）：许多慢性炎症性疾病，包括牙周感染，是由复杂的宿主相关微生物群落中持续存在的共生微生物介导的基于生物膜的病理学，确定指导生理状态（共生状态与致病状态）的环境线索。口腔厌氧菌是牙周病治疗策略开发的基础。最近的研究表明，厌氧菌 P.牙龈卟啉单胞菌不仅仅取决于其定植和增殖的能力；其生理状态及其在微生物群内的关联对于病理学的发展至关重要，此处提出的研究的中心假设是 L-精氨酸的可用性是一个关键信号。我们的初步研究表明，在 L-精氨酸耗尽的条件下，牙龈卟啉单胞菌下调表达。菌毛，抑制生物膜形成；相反，添加 L-精氨酸会促进菌毛表达和表面定植，因此，牙龈卟啉单胞菌会根据 L-精氨酸可用性的变化来调整其生活方式。其与其他细菌和宿主细胞相互作用的后续影响尚不清楚的是为什么 L-精氨酸对牙龈卟啉单胞菌如此重要，以及 L-精氨酸可用性的变化如何影响其。本应用的目的是确定牙龈卟啉单胞菌如何感知精氨酸的可用性以及它如何响应这种特定的氨基酸，并确定精氨酸对其与人类巨噬细胞和口腔上皮细胞相互作用的影响。对免疫至关重要的关键资源调节和牙龈卟啉单胞菌已经进化出具有感知和响应这种关键氨基酸的能力，不仅作为生长底物，而且作为持久性的基本策略，这些研究的基本原理是识别控制定植和定殖的信号。口腔病原体的生理状态将为开发治疗策略提供主要目标，因此，长期目标是确定这种信号传导机制是否可以用于治疗和预防人类生物膜引起的疾病。