Periodontitis is a polymicrobially-induced, chronic inflammatory disease of the tissues that support and surround the tooth. While greater than 500 organisms are found in dental plaque, Treponema denticola is one of only a few species associated with disease. It has been hypothesized that oral bacteria disrupt host homeostasis through manipulation of the innate immune system. In this study, we examine the impact of binding and subsequent cleavage of factor H, a complement regulator, by T. denticola in the evasion and subversion of complement. The molecular interaction between the sole FH-binding protein, FhbB, and FH was detailed by x-ray crystallography, site-directed mutagenesis, and inhibition analyses. Negatively-charged amino acids of FhbB formed salt-bridges with positively-charged residues of FH within the complement control protein domains (CCP) 6 and 7. In support of its critical role in disease, FhbB was universal among T. denticola isolates, although, different strains produce highly divergent FhbB proteins. Despite extensive sequence variation, predominantly within the FH-binding determinant, all FhbB proteins have similar structure and interact with FH using nearly identical molecular mechanisms. In addition to differences in FhbB, many isolates of T. denticola displayed significant variation in the activity of the chymotrypsin-like protease, dentilisin. Neither FhbB type produced nor dentilisin activity influenced serum resistance, as all strains tested were highly serum resistant. While sequence diversity of FhbB did not influence the interaction with FH or serum resistance, FhbB proteins elicited type-specific antibodies that blocked FH binding. Collectively, these analyses indicate that FH binding is an essential complement evasion mechanism of T. denticola and characterizes the uniquely complex interaction between T. denticola and complement. The data presented here provide novel insight into the pathogenesis of disease and begins to explore a hypothetical molecular mechanism by which this key periopathogen disrupts the host innate immune system, leading to periodontitis.
| Identifer | oai:union.ndltd.org:vcu.edu/oai:scholarscompass.vcu.edu:etd-4477 |
| Date | 01 January 2014 |
| Creators | Miller, Daniel Patrick |
| Publisher | VCU Scholars Compass |
| Source Sets | Virginia Commonwealth University |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | © The Author |
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