Among the key pathogens involved in oral bacterial diseases, Treponema denticola is the most invasive organism. The various oral Treponema bacterial species have in common a cytoplasmic structure with organizational similarities to intermediate filaments. In vitro experiments have demonstrated the importance of such structure in key events related to oral infectivity. The goal of this research is to decipher the importance and function of treponemal intermediate-like filaments in pathogenicity in vivo. The long-term goal is to develop new strategies to combat the invasive nature of treponemal cells, while maintaining a healthy oral microbiota. The rationale is to validate the hypothesis that treponemes propagation (colonization, persistence, and dissemination first local and then systemic) is dependent upon intermediate- like filaments. The proposed studies will focus on testing the pathogenicity of a genetically engineered T. denticola mutant deficient in intermediate-like filaments (cfpA knockout) in appropriate animal models to study oral infections. The infectivity of the cfpA knockout mutant will be tested in two mouse models. The first mouse model investigates the tissue and bone damage associated with an endodontic infection (Aim 1). The second mouse model tests the pathogenicity in a periodontal infection (Aim 2). In conjunction with the cfpA knockout mutant, the wild-type strain (live and formalin-killed) will be used as control, as well as a mutant deficient in motility to test the effect of live antigen presentation during the colonization step. The experimental quantitative endpoint is the measurement of bone loss at the root of the infected tooth in the endodontic model, and the recession of the alveolar bone crest from the cementoenamel junction in the periodontal model. A qualitative criterion is the inflammation associated with the infection, which is to be evaluated by histology of the center plane of the infected tooth in the endodontic infection model, and by cytokine production in the periodontal infection model. In the case of the periodontal infection model, an additional criterion will be the modification of the oral microbiota post-infection. This study will further our understanding of the pathogenesis of T. denticola in both periodontal and endodontic infections by providing a more complete understanding of the role of intermediate-like filaments in infectivity, the importance of motility for treponemes persistence, and model the biofilm population changes associated with periodontal disease. To allow the modulation of the oral biofilm, clinicians need new strategies to fight periodontal diseases. New strategies rely on an understanding of microbial biology. To limit bone loss and other damages, proper host responses and healthy natural biofilm should be promoted in the patient healing process. Our strategy is to target key functional entities of aggressive and invasive pathogens, with the goal of eliminating the damage- inducing population. ? ? ?
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