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; Korostoff, Jonathan M (2017) Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later. Periodontol 2000 75:116-151
Kajikawa, Tetsuhiro; Briones, Ruel A; Resuello, Ranillo R G et al. (2017) Safety and Efficacy of the Complement Inhibitor AMY-101 in a Natural Model of Periodontitis in Non-human Primates. Mol Ther Methods Clin Dev 6:207-215
Kajikawa, Tetsuhiro; Meshikhes, Fatimah; Maekawa, Tomoki et al. (2017) Milk fat globule epidermal growth factor 8 inhibits periodontitis in non-human primates and its gingival crevicular fluid levels can differentiate periodontal health from disease in humans. J Clin Periodontol 44:472-483
Hajishengallis, George; Reis, Edimara S; Mastellos, Dimitrios C et al. (2017) Novel mechanisms and functions of complement. Nat Immunol 18:1288-1298
Olsen, Ingar; Lambris, John D; Hajishengallis, George (2017) Porphyromonas gingivalis disturbs host-commensal homeostasis by changing complement function. J Oral Microbiol 9:1340085
Mitroulis, Ioannis; Chen, Lan-Sun; Singh, Rashim Pal et al. (2017) Secreted protein Del-1 regulates myelopoiesis in the hematopoietic stem cell niche. J Clin Invest 127:3624-3639
Makkawi, Hasnaa; Hoch, Shifra; Burns, Elia et al. (2017) Porphyromonas gingivalis Stimulates TLR2-PI3K Signaling to Escape Immune Clearance and Induce Bone Resorption Independently of MyD88. Front Cell Infect Microbiol 7:359
Hajishengallis, G; Krauss, J L; Jotwani, R et al. (2017) Differential capacity for complement receptor-mediated immune evasion by Porphyromonas gingivalis depending on the type of innate leukocyte. Mol Oral Microbiol 32:154-165
Maekawa, T; Kulwattanaporn, P; Hosur, K et al. (2017) Differential Expression and Roles of Secreted Frizzled-Related Protein 5 and the Wingless Homolog Wnt5a in Periodontitis. J Dent Res 96:571-577
Klotzsche-von Ameln, Anne; Cremer, Sebastian; Hoffmann, Jedrzej et al. (2017) Endogenous developmental endothelial locus-1 limits ischaemia-related angiogenesis by blocking inflammation. Thromb Haemost 117:1150-1163

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