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)
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Oral, Dental and Craniofacial Sciences Study Section (ODCS)
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Lunsford, Dwayne
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University of Pennsylvania
Schools of Dentistry
United States
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Hajishengallis, George; Moutsopoulos, Niki M (2016) Role of bacteria in leukocyte adhesion deficiency-associated periodontitis. Microb Pathog 94:21-6
Olsen, Ingar; Hajishengallis, George (2016) Major neutrophil functions subverted by Porphyromonas gingivalis. J Oral Microbiol 8:30936
Hajishengallis, George; Lamont, Richard J (2016) Dancing with the Stars: How Choreographed Bacterial Interactions Dictate Nososymbiocity and Give Rise to Keystone Pathogens, Accessory Pathogens, and Pathobionts. Trends Microbiol 24:477-89
Mastellos, D C; Ricklin, D; Hajishengallis, E et al. (2016) Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention. Mol Oral Microbiol 31:3-17
Subramanian, Pallavi; Mitroulis, Ioannis; Hajishengallis, George et al. (2016) Regulation of tissue infiltration by neutrophils: role of integrin α3β1 and other factors. Curr Opin Hematol 23:36-43
Hajishengallis, George; Moutsopoulos, Niki M; Hajishengallis, Evlambia et al. (2016) Immune and regulatory functions of neutrophils in inflammatory bone loss. Semin Immunol 28:146-58
Hajishengallis, George; Krauss, Jennifer L; Jotwani, Ravi et al. (2016) Differential capacity for complement receptor-mediated immune evasion by Porphyromonas gingivalis depending on the type of innate leukocyte. Mol Oral Microbiol :
Mastellos, Dimitrios C; Reis, Edimara S; Yancopoulou, Despina et al. (2016) From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage. Immunobiology 221:1046-57
Hajishengallis, George; Lambris, John D (2016) More than complementing Tolls: complement-Toll-like receptor synergy and crosstalk in innate immunity and inflammation. Immunol Rev 274:233-244
Maekawa, Tomoki; Briones, Ruel A; Resuello, Ranillo R G et al. (2016) Inhibition of pre-existing natural periodontitis in non-human primates by a locally administered peptide inhibitor of complement C3. J Clin Periodontol 43:238-49

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