Mary Ellen Davey Lab
Periodontal diseases are common chronic inflammatory diseases that afflict up to 50% of the adult population in the United States, and are associated with systemic diseases, such as rheumatoid arthritis, cardiovascular disease, diabetes, and Alzheimer’s disease. Annual direct costs for the prevention and treatment of these persistent infections are over $3.5 billion. Studies have shown that a shift to higher diversity and abundance of anaerobic bacteria within diseased gingival pockets is central to this disease, with the oral anaerobe Porphyromonas gingivalis being implicated as a primary pathogen.
Research in the Davey lab is focused on providing a better understanding of the pathogenicity and basic physiology of P. gingivalis. The virulence of P. gingivalis is not solely dependent on its ability to colonize and proliferate; instead, its physiological state and its associations with other subgingival bacteria direct development of a pathogenic community, leading to chronic inflammation of gingival tissues. Below are three key areas that are the current focus in the lab.
Surface translocation by P. gingivalis. To survive, many bacteria can switch between sessile growth and a motile mode in response to environmental, nutritional, and host-related cues. The Davey lab recently showed that P. gingivalis is capable of surface translocation and that arginine metabolism and type IX secretion are central to this process, yet how this process relates to its virulence is still under investigation. Our current goals are to determine how P. gingivalis senses arginine levels, how it responds to changes in L-arginine availability, and how changes in arginine levels affect biogenesis of outer membrane vesicles; and the ability of P. gingivalis to surface translocate, invade, and activate macrophages.
Regulatory mechanisms controlling expression of surface glycans. The primary goal of this project is to determine the regulatory mechanisms that control the synthesis and presentation of surface glycans and to determine how changes in the synthesis of surface glycans relates to P. gingivalis pathogenicity. Towards our goal, we have discovered that two DNABII proteins are involved in regulating the synthesis of K-antigen capsule. Bacterial DNABII family members function through their ability to both bind and bend and or stabilize nucleic acids. If binding of these histone-like proteins is disrupted, then DNA stability and transcription is affected, which directly impacts bacterial survival making these proteins potential targets for antimicrobials. Our studies have also identified an antisense RNA encoded within an unusual 77bp inverted repeat element. Our working model is that the interaction between two DNABII proteins and a 2-component response regulator with the 77bpIR element are central players in regulating synthesis of K-antigen capsule (an sphingolipids).
Sphingolipid biosynthesis by P. gingivalis. Although inflammation is central to periodontal disease pathogenesis, this inflammation is, paradoxically, insufficient to clear the source of infection. Thus, subversion of host immunity is central to the chronic nature of this disease. Research has shown that P. gingivalis is uniquely capable of targeted and dynamic immuno-suppression, yet we have limited knowledge of the underlying mechanisms. Remarkably, bacterial synthesis of sphingolipids (SLs) is almost entirely restricted to bacteria belonging to the phylum Bacteroidetes; and importantly many of these bacteria are commensals of mammals, where SLs are the basic building blocks of cell membranes and key signaling molecules (sphingosine-1-phosphate and ceramide). The overarching hypothesis of this line of research is that synthesis of lipids similar to the host affords P. gingivalis a mechanism of immune regulation. Dr. Davey’s studies in collaboration with Dr. Frank Gibson (University of Florida) have revealed that P. gingivalis releases SL-containing outer membrane vesicles (OMVs) that are immunosuppressive. The data suggest that SL-OMVs are an exquisite delivery system and form the basis of a mechanism of P. gingivalis-host communication. Currently, the focus is on determining when and how P. gingivalis synthesizes SLs and how SL-containing OMVs modulate the inflammatory response.