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 well as my transition to independence. By the end of my training plan, I will be well-positioned
to launch a productive independent career at the intersection of oral microbiology and immunology.