Project Summary/Abstract Research: Periodontitis (gum disease) is one of the most common inflammatory diseases worldwide, affecting nearly 50% of adults (65 million people) in the US alone. Untreated, it can destroy the tissues that support the teeth, eventually resulting in tooth loss. The cause of periodontitis is linked to the outgrowth of multiple, rather than individual, pathogens in the oral microbiota. For instance, co-detection of Aggregatibacter actinomycetemcomitans (Aa) with Filifactor alocis is a much greater predictor of future tissue destruction than detection of Aa alone. However, how Aa and F. alocis interact to elicit pathology while evading host immunity remains poorly understood. Microbiota-host interactions are often mediated by microbial metabolites, and a major metabolite of F. alocis is hydrogen sulfide, a toxic gas highly enriched in periodontitis. Based on my preliminary data, I hypothesize that F. alocis-derived sulfide triggers an immunological cascade that drives tissue destruction while constructing a niche for Aa to proliferate via sulfide-resistant anaerobic respiration. Of note, inexpensive, non-toxic drugs already exist that selectively inhibit anaerobic respiration (tungstate) or sequester sulfide (bismuth). To test my hypothesis and the therapeutic value of these drugs, I will dissect how F. alocis- derived sulfide impacts Aa (Aim 1) and the oral immune system (Aim 2) in complementary mouse models: thigh abscess, which allows for precise control over composition of the infecting community, and ligature-induced periodontitis, which allows for the assessment of oral immune responses. Through these Aims, I will potentially establish innovative therapies targeted against microbiota-host interactions that promote periodontal disease. Career Goals: My overarching goal as an independent investigator is to integrate the fields of oral microbiology and immunology as a strategy to gain novel insight into the etiology of periodontitis. To achieve this goal, I require additional training and knowledge in oral immunology as well as professional development in skills essential for leading a successful laboratory. Career Development Plan and Environment: My mentor Y. Belkaid, a renowned expert in microbiota-host interactions, is an investigator in the NIH Intramural Research Program, one of the largest research centers in the world. In this unique environment, I will directly benefit from the numerous resources in place to support my research project and career development, including microbiome and immunology core facilities, frequent seminars and opportunities to engage colleagues/mentors, and regular workshops on grant-writing, mentoring, and laboratory management. Furthermore, I have assembled a mentoring team who will complement my expertise in Aa and the abscess model by closely overseeing my training in the ligature model (NIDCR-based co-mentor N. Moutsopoulos) and F. alocis (collaborators R. Lamont and H. Fletcher) as...