Monday, October 2, 2023
10/2/2023
Project Summary/Abstract. Periodontitis, an inflammatory disease resulting in the degradation of the tooth supporting structures often leading to tooth loss, and a risk factor for many systemic diseases, affects over 700 million people worldwide with an estimated economic burden totaling $442 billion per year. A bacterial triad known as the `red-complex' comprising of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia is strongly implicated in the pathogenesis of the disease. However, it is not clearly understood why these three pathogens are so influential in the development of periodontitis. While these bacteria produce a number of factors to facilitate their colonization, undermine host immunity and promote subgingival polymicrobial synergy and dysbiosis, intriguingly, all three pathogens produce sialidase (neuraminidase) - an enzyme that can cleave terminal sialic acid from glycoproteins on the surface of epitheilial cells, immune cells and in salivary and gingival crevicular secretions. We hypotheisize that sialidase activity of these pathogens plays a critical role in the pathogenesis via disruption of structure-function activity of innate immune factors and liberation of sialic acid as a nutrient as well as a precursor for surface sialylation and synthesis of vital bacterial components such as peptidoglycan (bacterial cell-wall). In this application we will focus on the T. forsythia sialidase enzyme NanH as the prototypical pathogen enzyme with a unique contribution in the survival of T. forsythia - an organism auxotrophic for the peptidoglycan building block amino-sugar N-acetylmuramic acid (MurNAc). The NanH sialidase activity can promote early bacterial-epithelial cell interactions, cause disruption of innate immune responses and provide a means for the biosynthesis of MurNAc in biofilms and likely improves bacterium's survival in the subgingival niche by reducing its reliance on cohabiting bacteria to provide MurNAc and peptidoglycan fragments. Our hypothesis that sialic acid and peptidoglycan foraging activity of T. forsythia exacerbates periodontitis by promoting bacterial colonization, biofilm fitness, and host immune disruption will be addressed via: 1) Molecular level characterization of sialidase-host interactions, 2) Defining the metabolic fate of sialic acid and the impact of sialic acid utilization on peptidoglycan scavenging and pathogenesis, and 3) Determining the contribution of microbial sialidases in the modulation of polymicrobial ecology and inflammation while also examining the potential of anti- sialidase drugs such as FDA approved drugs TamiFlu (oseltamivir) in blocking periodontitis in a mouse model. This proposal will take an in-depth approach to define the influence of host sialoglycome-pathogen interactions from both the host and microbial standpoint. It will also focus on a novel sialo-peptidoglycan axis in T. forsythia and define how this axis might be critical for T. forsythia fitness. Further, as a proof of principle, it will test the therapeutic potential of pharmacological sialidase inhibitors in a mouse model to alleviate periodontal inflammation and remodel dysbiotic ecology back to health and improve periodontitis disease outcomes.
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