The goal of this research is to characterize the role of Treponema denticola surface proteins in interaction of
this human oral spirochete with host tissue, thereby gaining insight into mechanisms by which T. denticola
contributes to initiation and progression of periodontal disease. We focus on analysis of T. denticola protein
complexes that directly affect cells isolated from tissue comprising the periodontal ligament (PDL) that
comprises the junction between the tooth and the alveolar bone of the tooth socket: specifically the PrtP
lipoprotein protease complex (dentilisin) and the oligomeric Msp protein. Our overall hypothesis is that
dentilisin and Msp are major contributors to T. denticola cytopathic behavior in periodontal disease, In this
context we will examine specific domains of dentilisin and Msp, as well as the T. denticola lipooligosaccharide
component of the outer membrane. To characterize their specific roles in microbe-host interactions, our
approach is to utilize purified native and recombinant proteins as well as isogenic T. denticola strains carrying
defined mutations in individual components of these outer membrane complexes. We will first extend our
ongoing studies characterizing dentilisin and Msp assembly in the Td outer membrane. Then, to further studies
of host responses to challenge by Td and its specific components, we will then characterize in a cell model T.
denticola-induced dysregulation of TLR/MyD88 and Integrin/FAK signaling mechanisms and consequences for
the cytoskeleton as well as expression and activity of matrix metalloproteinases. We will determine the extent
to and the mechanisms by which specific T. denticola components contribute to tissue destruction in a mouse
model of periodontal disease. Finally, we will test the ability of the the antimicrobial peptide nisin to modulate T.
denticola-induced dysbiotic signaling in both the cell and animal models. Our research team is uniquely
positioned to conduct these studies, with combined expertise in spirochete molecular biology, extracellular
matrix biology and cytopathology of inflammatory diseases. Completion of this project will contribute to both
basic knowledge of spirochete molecular biology and to understanding of microbe-host interactions in chronic
infections such as periodontal diseases.