Microbial methylglyoxal promotes periodontal inflammation

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Project summary Tannerella forsythia is a leading pathogen implicated in periodontitis, a common chronic inflammation of the tooth-supporting apparatus (periodontium) that often results in tooth loss in adults. T. forsythia produces a highly reactive electrophilic compound methylglyoxal (MGO), which can chemically modify and cross-link biomolecules, disrupting their structure-function integrity. MGO causes the formation of what are known as the advanced glycation endproducts (AGEs), which can activate RAGE (receptor of AGEs) receptor, trigger a perpetuating pro-inflammatory, and pro-adhesive environment to drive tissue damage. The ability of T. forsythia to produce MGO is due to the presence of an enzyme, methylglyoxal synthase (MgsA), involved in the synthesis of MGO. Strikingly, the other two dominant periodontal pathogens implicated in periodontitis, namely Porphyromonas gingivalis and Treponema denticola, lack any homologs of this enzyme. It remains to be determined, however, if indeed microbially derived MGO from T. forsythia contributes to periodontal inflammation and what is the mechanistic basis of MGO-induced inflammation in the periodontium. In this study we will test the hypothesis that T. forsythia produced MGO by promoting AGEs is involved in the induction of a sustained inflammatory response detrimental to the periodontal tissues. We will test our hypothesis by completion of the following specific aims: 1) Molecular characterization of T. forsythia MGO modified host and bacterial proteins and 2) Determine the role of MGO in oral microbial dysbiosis and T. forsythia induced periodontitis. The study will increase our understanding of the pathogenic mechanisms of T. forsythia by elucidating the role of MGO as a novel virulent component of the bacterium. Overall, this knowledge might aid in designing new therapeutic approaches in improving oral and systemic health.