L-Arg Availability Affects the Physiological State of Porphyromonas gingivalis

 描述(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群介导的基于生物膜的病理。确定环境线索，指导口腔厌氧菌的生理状态(共生状态与致病状态)，是制定牙周病治疗策略的基础。最近的研究表明，厌氧菌P.gigivalis的致病潜力不仅仅取决于它的定植和增殖能力，它的生理状态和它在微生物群体中的联系是病理学发展的基础。这里提出的研究的中心假设是，L精氨酸的可获得性是指导牙龈假单胞菌的定植和毒力决定因素表达的关键信号。我们的初步研究表明，在L精氨酸耗尽的条件下，牙龈假单胞菌下调菌毛的表达，抑制生物膜的形成；相反，添加L精氨酸促进菌毛的表达和表面定植。因此，牙龈假单胞菌根据L精氨酸的可获得性变化调整其生活方式。此外，这种调整会对其与其他细菌和宿主细胞的相互作用产生后续影响。目前尚不清楚的是为什么L精氨酸是牙龈假单胞菌如此重要的氨基酸，以及L精氨酸可获得性的变化如何影响其生理功能。这项应用的目标是确定牙龈假单胞菌如何感知精氨酸的可用性以及它如何对这种特定的氨基酸做出反应，并确定精氨酸对其与人巨噬细胞和口腔上皮细胞相互作用的影响。我们假设精氨酸是一种对免疫至关重要的关键资源。 调控和牙龈假单胞菌已经进化出对这种关键氨基酸的感知和反应能力，不仅作为一种生长底物，而且作为一种持续存在的基本策略。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制定治疗策略提供主要目标。因此，长期目标是确定这种信号机制是否可以靶向治疗和预防人类生物膜引起的疾病。

 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.