Abstract Porphyromonas gingivalis is a major pathogen of severe adult periodontitis, a polymicrobial disease caused by the coordinated action of a complex microbial community that leads to inflammation of tissues supporting the teeth. A central hurdle limiting progress in periodontal disease research is the paucity of information detailing microbial signals that correlate with clinical progression at a site from health to disease. Filling this void, we recently reported metatranscriptome findings of the microbial community from human clinical samples during periodontal disease progression and discovered that CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-associated proteins in the periodontopathogen P. gingivalis were highly up-regulated only at those sites that progressed. CRISPRs-Cas systems are used by bacteria to prevent foreign DNA incorporation, as occurs with a viral attack. The goal of this research program is to understand the role that CRISPR-Cas systems have on virulence determinants of important periodontopathogens during disease progression. A comprehensive analysis of the mutants will provide information required to increase our understanding of not only CRISPR gene function, but also the contribution of these novel genes to virulence. To this end we propose the following Specific Aims: Aim 1. Identify targeted endogenous genes comparing transcriptome profiles of the wild-type and the mutants growing intracellularly. Aim 2. Determine the impact of CRISPR-associated genes on the innate immune host responses to P. gingivalis. Aim 3. Aim 3. Determine the role of CRISPR-Cas genes in the pathogenicity of P. gingivalis. We expect that this knowledge will facilitate the development of targeted approaches to prevent and treat periodontitis by inhibiting specific Cas proteins essential for virulence. Such results will fundamentally advance our understanding that such systems have in the metabolism of periodontal pathogens besides their traditional role assigned as a mechanism of protection against foreign DNA. We believe that the team we have assembled for this project has all the qualifications to accomplish successfully the goals proposed in the present application.