Periodontal disease will affect most individuals at some point in their life and its economic impact is enormous. Periodontitis results from a combination of host factors and a polymicrobial infection of normal flora origin. Disease results when an imbalance in numbers of each species develops. One contributor to periodontal disease is Treponema denticola (Td). We demonstrate that Td binds the complement regulatory protein, factor H like protein 1 (FHL-1) via an 11.5 kDa Td lipoprotein, designated, FhbB. FhbB is the only known protein produced by a microbial pathogen that specifically binds FHL-1 and not FH. This unique binding specificity provides possible insight into the biological rationale of FHL-1 binding by Td. In addition to its complement regulatory role, FHL-1 also has important cell adhesin and cell spreading activities. Several anchorage dependent cell lines have been demonstrated to bind to an FHL-1 matrix. The binding occurs through an RGD motif of FHL-1 that is located with a domain referred to as a short consensus repeat (SCR) 4. FHL-1 also interacts with the extracellular matrix (ECM) of tissue via this its RGD adhesion receptor recognition sequence. It is our hypothesis that the binding of cell or ECM anchored FHL-1 by the T. denticola FhbB protein plays a central role in several critical aspects of T. denticola pathogenesis including adherence, biofilm formation, tissue penetration and immune evasion. The studies proposed here fill an important niche in the study of T. denticola pathogenesis and of the biological role of FHL-1 binding by oral microflora and will advance our general understanding of the molecular mechanisms associated with the development and progression of periodontal disease.
The Specific Aims of this application are: 1: Analysis of fhbB expression and production in the human host and assessment of the anti- FhbB antibody response during periodontal disease;2: Identification of the molecular determinants of FhbB involved in FHL-1 binding;and 3) Analysis of the role of FhbB and FHL-1 binding in T. denticola pathogenesis through allelic exchange mutagenesis and complementation. General description: This application investigates a novel virulence mechanism employed by a causative agent of periodontal disease. The outcome of these analyses will allow for the development of new preventive and intervention strategies for periodontal disease.
|Miller, Daniel P; Oliver Jr, Lee D; Tegels, Brittney K et al. (2016) The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin. Infect Immun 84:2051-8|
|Fine, Lindy M; Miller, Daniel P; Mallory, Katherine L et al. (2014) The Borrelia hermsii factor H binding protein FhbA is not required for infectivity in mice or for resistance to human complement in vitro. Infect Immun 82:3324-32|
|Miller, D P; McDowell, J V; Bell, J K et al. (2014) Analysis of the complement sensitivity of oral treponemes and the potential influence of FH binding, FH cleavage and dentilisin activity on the pathogenesis of periodontal disease. Mol Oral Microbiol 29:194-207|
|Miller, D P; Frederick, J R; Sarkar, J et al. (2014) The Treponema denticola AtcR LytTR domain-containing response regulator interacts with three architecturally distinct promoter elements: implications for understanding the molecular signaling mechanisms that drive the progression of periodontal disease. Mol Oral Microbiol 29:219-32|
|Miller, D P; McDowell, J V; Rhodes, D V et al. (2013) Sequence divergence in the Treponema denticola FhbB protein and its impact on factor H binding. Mol Oral Microbiol 28:316-30|
|Miller, Daniel P; Bell, Jessica K; McDowell, John V et al. (2012) Structure of factor H-binding protein B (FhbB) of the periopathogen, Treponema denticola: insights into progression of periodontal disease. J Biol Chem 287:12715-22|
|Frederick, J R; Sarkar, J; McDowell, J V et al. (2011) Molecular signaling mechanisms of the periopathogen, Treponema denticola. J Dent Res 90:1155-63|
|McDowell, J V; Frederick, J; Miller, D P et al. (2011) Identification of the primary mechanism of complement evasion by the periodontal pathogen, Treponema denticola. Mol Oral Microbiol 26:140-9|
|Marconi, Richard T; McDowell, John V (2011) Tick salivary proteins offer the lyme disease spirochetes an easy ride and another way to hide. Cell Host Microbe 10:95-6|
|Miller, Daniel P; McDowell, John V; Bell, Jessica K et al. (2011) Crystallization of the factor H-binding protein, FhbB, from the periopathogen Treponema denticola. Acta Crystallogr Sect F Struct Biol Cryst Commun 67:678-81|
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