Treponema - Host Cell and Tissue Interactions

点击翻译按钮获取中文摘要

ABSTRACT 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.