Over the past several years, significant progress has been made in understanding of the etiology and pathogenesis of periodontal diseases. Nevertheless, the nature and contribution of the immune system to these disorders remain unclear. The basic hypothesis is that the immune system plays a primary role to minimize and/or prevent infection. Furthermore, the application posits that immunoregulatory abnormalities contribute to the pathogenesis of and susceptibility to periodontal disease. In this regard, the prior investigations have demonstrated that Fusobacterium nucleatum and Treponema denticola produce immunosuppressive proteins (ISPs). The fundamental hypothesis of the proposed studies is that periodontal pathogens produce ISPs that mediate local and/or systemic immunosuppression, thereby enhancing their own virulence and/or that of other opportunistic microorganisms. The plan is to focus this investigation on the F. nucleatum (Fip) and T. denticola (Sip) ISP which has been shown to induce human lymphocytes to arrest in the mid G 1 phase of the cell cycle. Moreover, the preliminary studies determined each ISP is composed of two subunits. The objectives of this application are to define the events responsible for ISP-induced G1 arrest and to determine the relationship between structure and function of the ISP subunits. The study is composed of four Specific Aims: 1) To determine the molecular mechanism(s) responsible for F. nucleatum (Fip) and 7' denticola (Sip) ISP-induced G1 arrest in human lymphocytes; 2) To determine if G1 arrest is irreversible resulting in activation of the G1 checkpoint and the apoptotic cascade; 3) To determine if Fip exists and functions as a heterodimer and examine the individual role of Fip A and Fip B in the induction of G 1 arrest; and 4) To determine if the two peptides that comprise the ISP of 7' denticola (Sip) are encoded by separate genes and, if so, to determine the functional role of each peptide.
| Shenker, Bruce J; Dlakic, Mensur; Walker, Lisa P et al. (2007) A novel mode of action for a microbial-derived immunotoxin: the cytolethal distending toxin subunit B exhibits phosphatidylinositol 3,4,5-triphosphate phosphatase activity. J Immunol 178:5099-108 |
| Lee, W; Pankoski, L; Zekavat, A et al. (2004) Treponema denticola immunoinhibitory protein induces irreversible G1 arrest in activated human lymphocytes. Oral Microbiol Immunol 19:144-9 |
