Tannerella forsythia remains a less studied and an enigmatic organism in comparison to other periodontal pathogens, even though clinical evidence increasingly implicates the organism in periodontitis. Additionally, in recent years T. forsythia has also been detected in endodontic infections and linked to systemic diseases. Difficulties in propagating this bacterium and the fact that it is quite resistant to genetic manipulations have made this bacterium less appealing to investigators. T. forsythia expresses a well- characterized TLR2 ligand, the BspA protein, and N- and O-glycan linked glycoproteins that comprise its surface (S) - layer, covering the outer membrane. The BspA protein and the bacterial glycans play critical roles in bacterial virulence. Specifically, S-layer glycans impact bacterial recognition by the antigen-presenting cells and modify their cytokine expression such that it results in the blockade of Th17 responses and neutrophil recruitment. This leads to increased bacterial persistence and colonization in the host. Concurrently, BspA and other ligands of T. forsythia induce TLR2 signaling favoring the development of Th2-type inflammatory responses detrimental to the alveolar bone.
The aim of this application is to understand the mechanisms by which T. forsythia exploits its surface glycans and TLR2 ligands to induce alveolar bone loss. To achieve our aim we propose to: (1) Define the interactions of T. forsythia S-layer glycans with macrophages and dendritic cells and the mechanisms leading to host immune modulation. We will test the hypothesis that the surface glycans by interacting with lectin-like receptors regulate cytokine responses and function of these cells, and;(2) Determine how theTLR2-Th2 axis contributes to T. forsythia-induced alveolar bone loss using a periodontitis mouse model. We will test the hypothesis that Th2 polarization triggers proliferation of RANKL expressing B cells, which eventually contributes to alveolar bone loss. Thus, our studies will delineate in detail the underlying mechanisms by which TLR2 ligation by bacterial ligands and S-layer glycoproteins orchestrate host immunity during T. forsythia-induced periodontal inflammation and will be fundamental to the development of preventive strategies against periodontitis in the future.
Periodontitis (severe form of gum disease) is a common bacterially induced inflammatory disease that often results in tooth loss in adults. The objective of this project is to understand in detail how an oral bacterium implicated in periodontitis undermines the host immune system to cause destruction of tooth supporting structures, with an emphasis on the role of bacterium's surface polysaccharides as immune modulators. Information gained from this study will potentially lead to the development of polysaccharide based immunotherapies including vaccines which will either improve the clinical outcomes of periodontitis or prevent the disease.
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|Settem, Rajendra P; Honma, Kiyonobu; Sharma, Ashu (2014) Neutrophil mobilization by surface-glycan altered Th17-skewing bacteria mitigates periodontal pathogen persistence and associated alveolar bone loss. PLoS One 9:e108030|
|Settem, R P; Honma, K; Nakajima, T et al. (2013) A bacterial glycan core linked to surface (S)-layer proteins modulates host immunity through Th17 suppression. Mucosal Immunol 6:415-26|
|Myneni, Srinivas R; Settem, Rajendra P; Sharma, Ashu (2013) Bacteria take control of tolls and T cells to destruct jaw bone. Immunol Invest 42:519-31|
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|Settem, Rajendra P; El-Hassan, Ahmed Taher; Honma, Kiyonobu et al. (2012) Fusobacterium nucleatum and Tannerella forsythia induce synergistic alveolar bone loss in a mouse periodontitis model. Infect Immun 80:2436-43|
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|Stafford, G; Roy, S; Honma, K et al. (2012) Sialic acid, periodontal pathogens and Tannerella forsythia: stick around and enjoy the feast! Mol Oral Microbiol 27:11-22|
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|Mishima, Elina; Sharma, Ashu (2011) Tannerella forsythia invasion in oral epithelial cells requires phosphoinositide 3-kinase activation and clathrin-mediated endocytosis. Microbiology 157:2382-91|
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