Oral spirochetes are present at high abundance in the subgingival dental plaque associated with severe periodontal lesions. Periodontitis affects up to 47% of the United States population in some form. Treponema denticola and other oral Treponema species colonize and thrive at the plaque-gingival tissue interface, in close association with neutrophils, the primary innate immune cells involved in the gingival tissue host response. The major outer sheath protein (Msp) is a prominent virulence factor produced by Treponema denticola that directly impairs neutrophil chemotaxis in vitro by modulation of lipid metabolites responsible for initiating the chemotactic process, mediated by active epitopes in the Msp protein. Many bacterial pathogens including oral spirochetes are known to produce outer membrane vesicles (OMVs) loaded with many bacterial components; including pathogenic membrane protein, such as Msp. OMVs are also now recognized as potent packages of virulence factors actively produced during infection with local and far-reaching pathogenic effects due to their small size and properties; which play key roles in bacterial survival and modulation of host response. However, there is still a significant gap in knowledge of the role of Msp in vivo as well as the functional and biological contribution of other oral Treponema species and OMVs in manipulating the neutrophil immune response. Likewise, there is a lack of efficient therapeutic molecules directed towards crucial spirochete virulence factors. Our central hypothesis is that oral spirochetes mediate impairment of neutrophil function through virulence factors with common functional properties. We will test our hypothesis by completion of the following specific aims: 1. Determine the potential of T. denticola Msp and the active epitopes to modulate neutrophil function in rodent-models of inflammation and periodontal disease 2. Assess Msp-like proteins from understudied oral spirochetes as novel virulence factors to impair neutrophil function and 3. Assess biogenesis of T. denticola OMVs as prominent virulence factors to impair neutrophil function. This work will advance our understanding of spirochete pathogenicity by examining common functionality of Msp proteins across oral treponema species, provide novel insight into the contribution of OMVs and the role of Msp in OMV function and interaction with neutrophils. Further, we also propose to develop potential therapeutic reagents directed towards Msp. Understanding how oral spirochete virulence factors render the neutrophil immune response ineffective and development of novel therapeutic tools to prevent this, is crucial to improving oral health. !