Abstract
The oral spirochete Treponema denticola is a keystone periodontal pathogen that, in association with members of a complex polymicrobial oral biofilm, contributes to tissue damage and alveolar bone loss in periodontal disease. Virulence-associated behaviors attributed to T. denticola include disruption of the host cell extracellular matrix, tissue penetration and disruption of host cell membranes accompanied by dysregulation of host immunoregulatory factors. T. denticola dentilisin is associated with several of these behaviors. Dentilisin is an outer membrane-associated complex of acylated subtilisin-family PrtP protease and two other lipoproteins, PrcB and PrcA, that are unique to oral spirochetes. Dentilisin is encoded in a single operon consisting of prcB-prcA-prtP. We employ multiple approaches to study mechanisms of dentilisin assembly and PrtP protease activity. To determine the role of each protein in the protease complex, we have made targeted mutations throughout the protease locus, including polar and nonpolar mutations in each gene (prcB, prcA, prtP) and deletions of specific PrtP domains, including single base mutagenesis of key PrtP residues. These will facilitate distinguishing between host cell responses to dentilisin protease activity and its acyl groups. The boundaries of the divergent promoter region and the relationship between dentilisin and the adjacent iron transport operon are being resolved by incremental deletions in the sequence immediately 5’ to the protease locus. Comparison of the predicted three-dimensional structure of PrtP to that of other subtilisin-like proteases shows a unique PrtP C-terminal domain of approximately 250 residues. A survey of global gene expression in the presence or absence of protease gene expression reveals potential links between dentilisin and iron uptake and homeostasis in T. denticola. Understanding the mechanisms of dentilisin transport, assembly and activity of this unique protease complex may lead to more effective prophylactic or therapeutic treatments for periodontal disease.
Highlights
Treponema denticola (Figure 1) is an oral spirochete that is a periodontal pathogen capable of inducing extensive host tissue damage (Loesche, 1988) in association with other members of a complex polymicrobial oral biofilm (Socransky et al, 1998; Hajishengallis, 2014)
T. denticola dentilisin is a unique lipoprotein complex implicated in a wide range of interactions with host tissue, cells and circulating immunomodulatory components
By focusing on the molecular mechanisms of expression and assembly of dentilisin, we hope to contribute to understanding of its role in periodontal pathogenesis at a mechanistic level
Summary
Treponema denticola (Figure 1) is an oral spirochete that is a periodontal pathogen capable of inducing extensive host tissue damage (e.g. chronic periodontitis) (Loesche, 1988) in association with other members of a complex polymicrobial oral biofilm (Socransky et al, 1998; Hajishengallis, 2014). Post-translational processing and interactions among the expressed proteins result in the formation of an active protease complex on the surface of T. denticola (Lee et al, 2002; Godovikova et al, 2011). Severe periodontitis lesions typically contain elevated levels of spirochetes, preferentially localized in intimate contact with tissue at the deepest regions of lesions (Sela, 2001). Spirochetes have both direct and indirect cytopathic effects contributing to both bacterial tissue penetration and destructive host responses (Lux et al, 2001; Chi et al, 2003). Bacterial factors that disrupt periodontal homeostasis are of prime interest as mediators of chronic local and systemic inflammatory challenge by oral organisms and as possible therapeutic targets
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