Date on Master's Thesis/Doctoral Dissertation
Microbiology and Immunology
Hajishengallis, George Nikos
Periodontal disease; Chemokine receptors; Innate immunity; Po gingivalis
Porphyromonas gingivalis; Periodontal disease; Natural immunity
Chronic periodontitis is strongly associated with composition of the oral biofilm occupying the gingival crevicular aspect of the tooth and its associated root. Some gram-negative, "red complex" bacteria instigate periodontal bone loss in patients, principal among these Porphyromonas gingivalis. P. gingivalis is a "late colonizer", indicating not only its physical location within the oral biofilm, but also the pathogenic dynamic of the interaction between P. gingivalis and the host innate immunity. Among several other subversive tactics, P. gingivalis has been shown to compel receptors vital to the orchestration of an appropriate immune response to co-associate and consequently signal in a way that directly benefits the pathogen. Upon interaction with human monocytes and murine macrophages, P. gingivalis has been shown to induce TLR2 and CXCR4 to co- associate in lipid rafts via its surface fimbriae. The ensuing crosstalk results in a cAMP dependent, PKA mediated inhibition of NF-KB which in turn leads to a state of mixed signals. TLR2 attempts to upregulate NF-KB as CXCR4 simultaneously signals to inhibit TLR2 antimicrobial signaling. Functionally, this was shown in human monocytes and mouse macrophages to cause downregulation of TNF-a and upregulation of IL-10. Here we show the interaction between P. gingivalis fimbriae and CXCR4 to have physiological relevance to the initiation and maintenance of periodontal bone resorption in a mouse model of infection. Pharmacologic inhibition of the P. gingivalis fimbriaeCXCR4 interaction prevented bone loss as well as halted progression of periodontal disease instigated prior to treatment in the Baker Model of oral infection. We also found that systemic administration of the bicyclam CXCR4 inhibitor AMD3100 leads to enhanced killing of P. gingivalis in a subcutaneous chamber model of infection. The subcutaneous chamber is an in vivo model system of the microaerophilic environment of the gingival pocket as well as the influx of dominantly comprised of neutrophils into the gingival crevice characteristic of chronic periodontitis. It is interesting that we noted that CXCR4 deficient mice display a similar host inflammatory profile to wild-type mice treated with AMD3100. However, while most of these mice were protected from P. gingivalis-mediated bone loss, one of the CXCR4 deficient mice did not demonstrate protection from alveolar bone loss when chronically infected with P. gingivalis. These mice also showed a healthier inflammatory profile compared to their infected, untreated counterparts. Thus, the results below indicate that AMD3100 effectively inhibits periodontal bone loss due to the ability of the compound to counter P. gingivalis' VI recognition of CXCR4. This provides evidence supporting the importance of this coreceptor in developing therapeutic strategies for treating periodontal disease.
Mc Intosh, Megan L., "Blockade of CXCR4 inhibits Porphyromonas gingivalis colonization in vivo and subsequent periodontal bone loss." (2012). Electronic Theses and Dissertations. Paper 932.