Multiple Functions of Glutathione Catabolism and H2S in T. denticola Pathogenesis

  • Chu, Lianrui (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): In diseased periodontal pockets, glutathione levels are lower than in healthy sites and the amount of H2S is higher. It has been assumed, but not proven, that changes in the concentrations of these thiol-compounds are important for the tissue pathology seen in periodontitis. Although the mechanism by which the levels of glutathione and H2S are perturbed in diseased pockets is unknown, the consensus is that bacteria play a key role. Thus, we have been studying the ability of periodontal pathogens to produce H2S from glutathione since such a metabolic pathway could alter the levels of these two molecules in the gingival crevice. We have focused on the major periodontal pathogen Treponema denticola and have shown previously that it can catabolize glutathione to H2S via a three step enzymatic pathway (GTSP). Our goal is to elucidate the role of such thiol catabolic pathways, and the metabolites they use and produce, in periodontal pathology. To this end, we have conducted several preliminary experiments with the following relevant results: (1) T. denticola plus glutathione can induce apoptosis in human gingival fibroblasts and periodontal ligament cells in vitro. (2) Periodontal ligament cell synthesis of proinflammatory cytokines is increased by T. denticola plus glutathione in vitro. (3) Glutathione exacerbates the lesion size caused by T. denticola in a mouse abscess model. (4) T. denticola enhances alveolar bone resorption in rats and decreases gingival crevicular fluid glutathione levels. (5) Most significantly, we recently constructed a T. denticola deletion mutant in the first gene (ggt) of the GTSP. This mutant cannot convert glutathione into H2S. Thus, we are uniquely positioned to test the hypothesis that the decrease in glutathione levels by bacterial metabolism, specifically the T. denticola GTSP, and the accompanying increase in H2S production will play key roles in the host tissue damage seen in periodontitis. In Aim 1, we will use wild type T. denticola and our ?ggt mutant to demonstrate that the GTSP, particularly its generation of H2S, enhances apoptosis in periodontal cells and modulates the levels and pattern of cytokines produced by host cells in vitro. Most importantly, the T. denticola mutant will be used in two animal models (Aim 2) to prove that a bacterium's ability to lower glutathione and increase H2S is critical for causing tissue/bone pathology in vivo. The rat model of alveolar bone loss will also be used to test the ability of three GTSP inhibitors, which we have already characterized in vitro, to limit T. denticola pathogenesis in vivo. The outcomes of the proposed studies will prove, for the first time, that a bacterium's ability to influence glutathione and H2S levels in the subgingival crevice is a significant contributor to periodontal tissue damage. Although the experiments are only being done with T. denticola, the results would establish a new paradigm whereby the physiology of periodontal bacteria, singly or synergistically, could perturb thiol-molecule homeostasis to cause disease pathology. Re-establishing normal periodontal pocket metabolite levels pharmacologically by inhibiting a bacterial catabolic pathway could be an innovative strategy to reduce host damage in periodontitis.
StatusFinished
Effective start/end date5/1/144/30/17

Funding

  • National Institutes of Health: $373,750.00
  • National Institutes of Health: $373,750.00

ASJC

  • Medicine(all)
  • Dentistry(all)

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