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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE014749-10A1
Application #
8759749
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
2002-07-01
Project End
2019-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Dentistry
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Settem, R P; Honma, K; Shankar, M et al. (2018) Tannerella forsythia-produced methylglyoxal causes accumulation of advanced glycation endproducts to trigger cytokine secretion in human monocytes. Mol Oral Microbiol 33:292-299
Dong, Youyi; Zhang, Celia; Frye, Mitchell et al. (2018) Differential fates of tissue macrophages in the cochlea during postnatal development. Hear Res 365:110-126
Ruscitto, A; Sharma, A (2018) Peptidoglycan synthesis in Tannerella forsythia: Scavenging is the modus operandi. Mol Oral Microbiol 33:125-132
Honma, Kiyonobu; Ruscitto, Angela; Sharma, Ashu (2017) ?-glucanase activity of the oral bacterium Tannerella forsythia contributes to the growth of a partner species, Fusobacterium nucleatum, in co-biofilms. Appl Environ Microbiol :
Chinthamani, Sreedevi; Settem, Rajendra P; Honma, Kiyonobu et al. (2017) Macrophage inducible C-type lectin (Mincle) recognizes glycosylated surface (S)-layer of the periodontal pathogen Tannerella forsythia. PLoS One 12:e0173394
Friedrich, Valentin; Janesch, Bettina; Windwarder, Markus et al. (2017) Tannerella forsythia strains display different cell-surface nonulosonic acids: biosynthetic pathway characterization and first insight into biological implications. Glycobiology 27:342-357
Vinogradov, Evgeny; St Michael, Frank; Homma, Kiyonobu et al. (2017) Structure of the LPS O-chain from Fusobacterium nucleatum strain 10953, containing sialic acid. Carbohydr Res 440-441:38-42
Ruscitto, Angela; Hottmann, Isabel; Stafford, Graham P et al. (2016) Identification of a Novel N-Acetylmuramic Acid Transporter in Tannerella forsythia. J Bacteriol 198:3119-3125
Honma, Kiyonobu; Ruscitto, Angela; Frey, Andrew M et al. (2016) Sialic acid transporter NanT participates in Tannerella forsythia biofilm formation and survival on epithelial cells. Microb Pathog 94:12-20
Stafford, Graham P; Chaudhuri, Roy R; Haraszthy, Violet et al. (2016) Draft Genome Sequences of Three Clinical Isolates of Tannerella forsythia Isolated from Subgingival Plaque from Periodontitis Patients in the United States. Genome Announc 4:

Showing the most recent 10 out of 35 publications