Folate-Modulated Virulence of Porphyromonas gingivalis

叶酸调节牙龈卟啉单胞菌的毒力

• 批准号: 10491743
• 负责人: Kendall Stocke
• 金额: $ 6.84万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491743
• 关键词: Abscess; Alveolar Bone Loss; Amino Acids; Antibiotics; Aspergillus fumigatus; Bacteria; Carbon; Communities; Complex; Development; Disease; Environment; Folic Acid; Folic Acid Antagonists; Folic Acid Deficiency; Gene Expression; Goals; Growth; Human; Immune response; Infection; Infection prevention; Innate Immune Response; Link; Literature; Measures; Metabolic; Metabolic Pathway; Metabolism; Microbe; Modeling; Mus; NADH; NADP; Neutrophil Infiltration; Nutrient; Nutritional; Oral; Oral cavity; Organism; Pathogenicity; Pathway interactions; Patients; Peptide Hydrolases; Periodontal Diseases; Porphyromonas gingivalis; Production; Property; Purines; Pyrimidines; Reaction; Reporting; Series; Streptococcus gordonii; Streptococcus pneumoniae; Study models; Sulfonamides; Thromboplastin; Trimethoprim; Virulence; Virulence Factors; Virulent; antimicrobial; bacterial metabolism; base; chemokine; co-infection; cytokine; dihydrofolate; experimental study; folic acid metabolism; gene synthesis; gingipain; insight; metabolic phenotype; metabolomics; microbial; mouse model; mutant; novel; nutrition; pathogen; periodontopathogen; synthetic enzyme; transcriptome sequencing

Periodontal disease, one of the most common infections of humans, is driven by pathogens that influence the composition and trajectory of the oral polymicrobial community. These pathogens can take hold in an inhospitable environment and pave the way for other organism to colonize and grow. A key factor in allowing a pathogen to establish itself and colonize despite these odds is successfully regulating the expression of virulence factors while acquiring enough essential nutrition for replication and growth. One such essential nutrient is folate, which is classically linked to modulation of virulence in microbes. Although the literature has shown that limiting folate availability leads to decreased virulence in many microbes, however, we have found a clear exception to this rule in the periodontal pathogen P. gingivalis, an asaccharolytic organism that uses an amino-acid based metabolism. As a model for studying how folate availability regulates virulence in asaccharolytic pathogens, we are investigating how restricting the ability of P. gingivalis to produce folate regulates its expression of virulence factors. The objectives of this study are to: i) define the metabolic phenotype of P. gingivalis induced by folate deficiency; ii) determine how the metabolic phenotype of P. gingivalis is associated with the expression of virulence factors; and iii) characterize the host immune response to folate-deficient P. gingivalis. The completion of this study will provide critical insight into how limiting folate availability does not universally suppress the virulence of pathogens, but has the potential to result in enhanced virulence in asaccharolytic pathogens. We will also provide novel information on how the flux of metabolites in the folate and one-carbon metabolic pathways are associated with virulence in P. gingivalis and how this could apply to other organisms utilizing non-carbohydrate based metabolisms. Our overall long-term goal is to apply these findings to refine when it is appropriate to use antifolates to treat microbial infections and reduce overall harm caused to patients. Further, these findings will help narrow down alternative pathways to target treatments for infections caused by asaccharolytic pathogens.

牙周病是人类最常见的感染之一，由影响牙周病的病原体引起 口腔多菌群落的组成和发展轨迹。这些病原体可以在不适宜居住的地方滋生 环境，并为其他生物的定居和生长铺平道路。一个关键因素是允许病原体 尽管存在这些困难，但建立和定居成功地调节了毒力因子的表达 同时获得足够的复制和生长所需的营养。其中一种重要的营养物质是叶酸，它 传统上与微生物的毒力调节有关。尽管文献表明，限制叶酸 可获得性导致许多微生物的毒力降低，然而，我们发现了一个明显的例外 牙周病原体P.gigivalis的规则，它是一种利用氨基酸为基础的无糖微生物 新陈代谢。作为研究叶酸供应如何调节阿糖分解病原体毒力的模型，我们 正在研究限制牙龈假单胞菌产生叶酸的能力是如何调节其毒力表达的 各种因素。本研究的目的是：1)确定叶酸诱导的牙龈假单胞菌的代谢表型 缺乏；ii)确定牙龈假单胞菌的代谢表型与 毒力因子；以及iii)表征宿主对叶酸缺乏的牙龈假单胞菌的免疫反应。完成度 这项研究将提供关键的洞察力，以了解限制叶酸供应如何不能普遍抑制 病原体的毒力，但有可能导致阿糖类分解病原体的毒力增强。我们 还将提供有关叶酸和一碳代谢途径中代谢物的流量如何的新信息 与牙龈假单胞菌的毒力有关，以及这如何适用于利用非碳水化合物为基础的新陈代谢的其他生物。我们的总体长期目标是将这些发现应用于在 适当使用抗叶酸治疗微生物感染，减少对患者的整体伤害。此外， 这些发现将有助于缩小针对由以下原因引起的感染的治疗的替代途径 不含糖的病原体。