From Symbiosis to Dysbiosis and Back: The Impact of Pro-Inflammation and Pro-Resolution

Periodontitis is initiated by oral bacteria, but quickly transits to an inflammatory immune disease with loss of host- bacterial homeostasis. Homeostasis, the symbiotic balance between host tissues and the resident periodontal microbiome is disrupted by a dysregulated immune response. From symbiosis to dysbiosis, early innate immune components are robustly linked. At the host-microbial interface, we have ample evidence that microbes trigger the immune response but lack knowledge of how the immune response regulates the composition and functional activity of the microbiome. Specialized Pro-resolving Mediators (SPMs) are a family of eicosanoid lipid mediators that bind to specific cell receptors to coordinate the return of an inflammatory lesion to homeostasis. Among the many SPMs, E-series resolvins are naturally occurring metabolites of transformation circuits of the omega-3 fatty acid, eicosapentaenoic acid (EPA), that actively induce resolution of inflammation. Activation of the Resolvin E1 (RvE1) receptor (ERV1) in gain-of-function studies with the ERV1 transgenic mouse (ERV1tg), show profound resistance to periodontitis. The use of resolvins to control inflammation allows us to test our central hypothesis that early immune activation directly contributes to the development of periodontal dysbiosis, which can be re- versed/prevented by activating Resolivin-E1 mediated resolution of inflammation pathways. To test this hypoth- esis, we break our investigations into two levels. First, in a murine model, we will characterize the oral microbi- ome’s functional and spatial organizational changes as symbiosis transits to dysbiosis. Second, we will use an in vitro system to unravel the mechanisms that determine how RvE1 and its receptor (ERV1) influence the dy- namics of dysbiosis and inflammatory/immune responses in periodontitis. The candidate is a DDS/PhD perio- dontist who is committed to an academic career dedicated to improving periodontal and oral health. The men- tored phase of the proposal will be carried out with Dr. Thomas Van Dyke (Primary mentor) and Dr. Xuesong He (Co-mentor) at the Forsyth Institute. The goal of the K99 phase is to provide additional training, mentoring, and experience in three important areas 1) advanced bioinformatics training for microbiome data; 2) study design and biostatistics training; and 3) career development. A strong Scientific Advisory Committee from the Forsyth Institute, Harvard Medical School, and the University of Washington has been established with diverse expertise in immunology, microbiology, bioinformatics, and statistics to help guide the candidate providing a training plan that complements and expands her scientific background with mentors whose expertise spans the broad scope of the scientific problem. The scientific component and training outlined in this proposal provide a pathway for the candidate to transit to an independent research career in a tenure track faculty position independent of the research programs of the mentors. Successful completion of this project will lead to better understanding of host-microbiome interactions and how to gain control of the inflammation/dysbiosis cycle in periodontitis to ame- liorate disease. 1