T. denticola is an important periodontal pathogen. The cellular mechanisms responsible for the recognition of T. denticola by the innate immune system are not currently resolved. Our long-term goal is to elucidate the cellular receptors of the host responsible for the recognition of T. denticola, as well as its periplasmic flagella (PFs) and major surface protein (Msp) by the innate immune system and how the engagement of the TLR pathways are regulating the inflammatory response. Our hypothesis is: the ability of T. denticola whole cells, PFs, and Msp to interact with Toll-like receptors (TLRs), specifically TLR2, expressed on immune cells is a major mechanism responsible for the pathogenesis of this organism by regulating the induction, nature, and magnitude of the host's inflammatory response. This hypothesis is based on 1) a direct comparison of immune cells isolated from wild-type and TLR2-deficient mice demonstrated that the levels of the pro-inflammatory cytokine, TNF-alpha was significantly different when stimulated with T. denticola, 2) stimulation of immune cells from TLR2-deficient mice with T. denticola did not result in detectable levels of TNF-alpha production; thus demonstrating that TLR2 is responsible for mediating innate immune responses to T. denticola whole cells; 3) stimulation of wild-type and TLR4-deficient cells with T. denticola resulted in similar levels of TNF-alpha; thus demonstrating that TLR4 is not involved in mediating cellular responses to T. denticola; 4) isogenic mutants HL51 (lacks PFs) and MHE (lacks Msp) had >60% and 30% reduction in TNF-alpha levels, respectively, as compared to wild-type T. denticola cells. These experimental observations have led to the basis of the current proposal to focus on the specific role of TLR2 in mediating the host's innate immune response to T. denticola. We propose to characterize the functional ability of TLR2 (in conjunction with TLR1, TLR6, or both) to mediate the production of pro- and anti-inflammatory cytokine production in response to T. denticola, its PFs and Msp. Specifically, with the aid of TLR-(initially 1, 2, and 6) knockout mice: (a) we will determine how TLR2 is involved in mediating cellular responses to T. denticola and its isogenic mutants HL51 and MHE; and (b) identify how these specific factors associated with T. denticola, e.g. PFs and Msp, mediate host inflammatory responses. ? ?
| Ruby, John; Martin, Michael; Passineau, Michael J et al. (2018) Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2. Infect Immun 86: |
| Li, Yuebin; Ruby, John; Wu, Hui (2015) Kanamycin Resistance Cassette for Genetic Manipulation of Treponema denticola. Appl Environ Microbiol 81:4329-38 |
| Ruby, J D; Lux, R; Shi, W et al. (2008) Effect of glucose on Treponema denticola cell behavior. Oral Microbiol Immunol 23:234-8 |
| Ruby, John; Rehani, Kunal; Martin, Michael (2007) Treponema denticola activates mitogen-activated protein kinase signal pathways through Toll-like receptor 2. Infect Immun 75:5763-8 |
