Mechanisms of neutrophil impairment by Treponema denticola

? DESCRIPTION (provided by applicant): Treponema denticola is an oral spirochete present in the subgingival dental plaque associated with severe periodontal lesions. T. denticola colonizes and thrives at the plaque-gingival tissue interface, in close association with neutrophils, the primary innate immune cells contributing to the first line of host defense in the gingival tissue. The major outer sheath protein (Msp) is a prominent virulence factor of T. denticola that directly impairs neutrophil function including directed migration (chemotaxis). Msp impairs neutrophil chemotaxis by modulating the production of phospholipid signalling molecules that initiate the migratory process. However, there is still a significant gap in knowledge of how T. denticola Msp orchestrates inhibition of neutrophil chemotaxis. Our central hypothesis is that T. denticola Msp possesses functional regions that similarly to the entire Msp molecule, are responsible for manipulation of phospholipid modifying enzymes. We will test our hypothesis by completion of the following specific aims: 1. Identify the functional regions of Msp that inhibit neutrophil chemotaxis and associated signalling pathways and 2. Identify initial Msp-mediated neutrophil signalling events involved in dysregulation of phospholipid modifying enzymes. This work will advance our understanding of T. denticola pathogenicity through identification of initial phospholipid- related signalling events involved in neutrophil evasion and Msp protein regions involved. Understanding how oral spirochete virulence factors render the neutrophil immune response ineffective to allow for sustained bacterial survival is key to future development of new therapeutic approaches.