Innate immunity plays a central role in infection-driven inflammatory conditions, including periodontitis which is one of the most common chronic disorders of infectious origin in humans. However, successful microbial pathogens, such as the periodontopathogen Porphyromonas gingivalis, have evolved mechanisms which proactively manipulate the innate immune response. Subversion of innate immunity may additionally undermine the overall host defense, since the innate immune response plays an instructive role in adaptive immunity. This research proposal has been designed to investigate and elucidate molecular mechanisms whereby P. gingivalis modifies innate immune signaling pathways leading to increased virulence and persistence within the host. Although innate recognition and signaling in response to P. gingivalis is primarily mediated by the Toll-like receptor 2 (TLR2)-centered pattern recognition apparatus, preliminary studies indicate that this periodontal pathogen instigates the association of the chemokine receptor CXCR4 with TLR2 resulting in cross-talk and altered signaling downstream of TLR2. On the basis of additional preliminary evidence, the overall hypothesis is that P. gingivalis, through its cell surface fimbriae, exploits CXCR4 and manipulates TLR2 intracellular signaling in ways that suppress the proinflammatory/antimicrobial pathway but enhance a distinct proadhesive pathway;both of these activities have the potential to increase the survival capacity of the pathogen, thereby prolonging P. gingivalis infection and potentiating its impact on periodontal disease. In vitro immunological approaches using transfected cell lines or primary macrophages will elucidate the mechanistic basis of TLR2/CXCR4 cross-talk, which is hypothesized to involve the cAMP-dependent protein kinase A. Moreover, the biological significance of the putative exploitation of CXCR4 by P. gingivalis will be investigated using a mouse periodontitis model, in which a CXCR4 antagonist (AMD3100) is expected to suppress P. gingivalis virulence. The long-term objective of investigating CXCR4-dependent mechanisms whereby P. gingivalis manipulates TLR2 signaling is to identify effective antagonists for redirecting the innate response to benefit the host. The fight against HIV and AIDS has produced a number of drugs including CXCR4 antagonists, which are available for investigation in other formidable diseases where CXCR4 may play a pathophysiological role. Such CXCR4 antagonists may find therapeutic application in human periodontitis.

Public Health Relevance

Periodontitis is one of the most common chronic disorders of infectious origin in humans, and is also associated with systemic diseases such as atherosclerosis. This research proposal presents evidence that the periodontal pathogen P. gingivalis exploits a host receptor, namely CXCR4, for undermining host defense and promoting its virulence. We believe that CXCR4 antagonists may find therapeutic application in human periodontitis and, in this context;we will test a CXCR4 antagonist (AMD3100) for its ability to inhibit P. gingivalis-induced periodontitis in a mouse model.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
Project #
Application #
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pennsylvania
Schools of Dentistry
United States
Zip Code
Lamont, Richard J; Hajishengallis, George (2015) Polymicrobial synergy and dysbiosis in inflammatory disease. Trends Mol Med 21:172-83
Hajishengallis, George (2015) Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol 15:30-44
Mitroulis, Ioannis; Alexaki, Vasileia I; Kourtzelis, Ioannis et al. (2015) Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther 147:123-35
Choi, E Y; Lim, J-H; Neuwirth, A et al. (2015) Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol Psychiatry 20:880-8
Hajishengallis, George (2014) Aging and its Impact on Innate Immunity and Inflammation: Implications for Periodontitis. J Oral Biosci 56:30-37
Maekawa, Tomoki; Krauss, Jennifer L; Abe, Toshiharu et al. (2014) Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 15:768-78
Hajishengallis, E; Hajishengallis, G (2014) Neutrophil homeostasis and periodontal health in children and adults. J Dent Res 93:231-7
Hajishengallis, G; Sahingur, S E (2014) Novel inflammatory pathways in periodontitis. Adv Dent Res 26:23-9
Maekawa, Tomoki; Abe, Toshiharu; Hajishengallis, Evlambia et al. (2014) Genetic and intervention studies implicating complement C3 as a major target for the treatment of periodontitis. J Immunol 192:6020-7
Moutsopoulos, Niki M; Konkel, Joanne; Sarmadi, Mojgan et al. (2014) Defective neutrophil recruitment in leukocyte adhesion deficiency type I disease causes local IL-17-driven inflammatory bone loss. Sci Transl Med 6:229ra40

Showing the most recent 10 out of 70 publications