Folate-Modulated Virulence of Porphyromonas gingivalis

牙周病是人类最常见的感染之一，是由病原体驱动的， 口腔多微生物群落的组成和轨迹。这些病原体可以在一个不适合居住的 环境，并为其他生物的殖民和生长铺平道路。一个关键因素是让病原体 尽管存在这些困难，但它仍能自我建立并定植，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必需的营养。其中一种必需营养素是叶酸， 与微生物毒力的调节有关。尽管文献表明限制叶酸 然而，我们发现了一个明显的例外， 牙周病原体牙龈卟啉单胞菌中的规则，牙龈卟啉单胞菌是一种使用基于氨基酸的 新陈代谢.作为研究叶酸利用率如何调节溶砷病原体毒力的模型，我们 正在研究限制牙龈卟啉单胞菌产生叶酸的能力如何调节其毒力的表达 因素本研究的目的是：i）确定叶酸诱导的牙龈卟啉单胞菌代谢表型 ii）确定牙龈卟啉单胞菌的代谢表型如何与 毒力因子;和iii）表征对叶酸缺乏的牙龈卟啉单胞菌的宿主免疫应答。完成 这项研究的结果将提供关键的见解，如何限制叶酸的可用性并没有普遍抑制 病原体的毒力，但有可能导致溶血性病原体的毒力增强。我们 还将提供新的信息，如何在叶酸和一碳代谢途径的代谢物流量 与牙龈卟啉单胞菌的毒力有关，以及这如何适用于利用非碳水化合物代谢的其他生物体。我们的总体长期目标是应用这些发现来完善， 因此，使用抗叶酸剂治疗微生物感染并减少对患者造成的总体伤害是适当的。此外，本发明还 这些发现将有助于缩小替代途径，以针对由以下原因引起的感染进行治疗： 溶砷病原体

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.