L-Arg Availability Affects the Physiological State of Porphyromonas gingivalis

 描述（由申请人提供）：许多慢性炎症性疾病，包括牙周感染，是由复杂宿主相关微生物群落中持续存在的肠道微生物群介导的基于生物膜的病理。确定指导口腔厌氧菌的生理状态（牙周与致病状态）的环境线索，是牙周病治疗策略发展的基础。最近的研究表明，厌氧菌牙龈卟啉单胞菌的致病潜力不仅仅取决于其定殖和增殖的能力;其生理状态及其在微生物聚生体中的关联是病理学发展的基础。本文提出的研究的中心假设是，L-精氨酸的可用性是指导牙龈卟啉单胞菌中毒力决定簇定殖和表达的关键信号。我们的初步研究表明，在L-精氨酸耗尽条件下，牙龈卟啉单胞菌下调菌毛的表达，抑制生物膜形成;相反，添加L-精氨酸促进菌毛的表达和表面定殖。因此，牙龈卟啉单胞菌调整其生活方式，以响应L-精氨酸可用性的变化。此外，这种调整对它与其他细菌和宿主细胞的相互作用有后续影响。目前尚不清楚的是为什么L-精氨酸是牙龈卟啉单胞菌如此重要的氨基酸，以及L-精氨酸可用性的变化如何影响其生理学。本申请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巨噬细胞和口腔上皮细胞相互作用的影响。我们认为精氨酸是一种重要的免疫资源， 牙龈卟啉单胞菌已经进化出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，识别控制口腔病原体定植和生理状态的信号将为治疗策略的开发提供主要目标。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诱导的疾病。

 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.