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：
9011518
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/9011518
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 Targeting Genes Genetic Screening Germ-Free Gingiva Goals Growth Health 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 clinically relevant commensal microbes cost experience fimbria genetic regulatory protein inflammatory bone loss keratinocyte macrophage microbial microbial community microbiota monocyte mouse model mutant oral anaerobes oral commensal oral pathogen oral streptococci pathogen primitive cell promoter response skills subgingival biofilm targeted treatment therapeutic development transcriptome 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（由适用提供）：许多慢性炎症性疾病，包括牙周感染，都是基于生物膜的病理，由共生微生物群介导的复杂宿主相关微生物群落中。确定指导口腔厌食症的物理状态（共生与致病状态）的环境线索，这对于牙周疾病的治疗策略的发展至关重要。最近的研究表明，厌氧细菌的致病潜力不仅取决于其定殖和增殖的能力。它的物理Stte及其在微生物财团内的关联是病理发展的基础。这里提出的研究的中心假设是，L-精氨酸的可用性是指导牙龈疟原虫中病毒定植和表达的关键信号。我们的初步研究表明，在L-精氨酸耗尽条件下，牙龈疟原虫下降调节叶片的表达，抑制生物膜的形成。相反，添加L-精氨酸的添加会增强叶片和表面定植的表达。那就是牙龈疟原虫会根据L-精氨酸的可用性变化来调整其生活方式。此外，这种调整对其与其他细菌和宿主细胞的相互作用产生了后续影响。尚不清楚的是为什么L-精氨酸对牙龈疟原虫是如此重要的氨基酸，以及L-精氨酸可用性的变化如何影响其生理。该应用的目的是确定牙龈疟原虫如何感觉到精氨酸的可用性及其对该特定氨基酸的反应，并确定精氨酸对其与人类巨噬细胞和口服上皮细胞相互作用的影响。我们肯定精氨酸是对免疫至关重要的关键资源调节和牙龈疟原虫以感知和响应这种关键氨基酸的能力而发展，不仅是生长底物，而且是持久性的基本策略。这些研究的理由是，确定控制定植和口腔病原体的物理状态的信号将为发展治疗策略的发展提供主要目标。这是长期目标是确定这种信号传导是否可以针对人类的生物膜诱导的疾病的治疗和预防。