Polymicrobial infections are inherently more complex than mono-species infections, and this complexity has been a significant barrier to both a fuller appreciation of pathogenic mechanisms, and to the development of effective measures to control or prevent the disease. Periodontal diseases typify polymicrobial diseases, and are among the most common infections of humans. Although certain organisms, such as Porphyromonas gingivalis, are considered key pathogens, it is the polymicrobial community as a whole that initiates and drives the disease. While interspecies interactions within communities shape overall pathogenic potential, study of virulence mechanisms has been largely restricted to individual organisms in monoculture. In this proposal we will molecularly dissect the mechanistic basis of polymicrobial interactions in a model community of P. gingivalis with the antecedent colonizer S. gordonii. Our preliminary data have established multimodal interactions between P. gingivalis and S. gordonii. Detection of the streptococcal metabolite 4 aminobenzoate (pABA) by P. gingivalis, or interactions between the Mfa1 fimbriae and the streptococcal SspA/B surface protein, incite disparate signaling events that are transduced through a tyrosine kinase/phosphatase signal integration hub. In vivo colonization is enhanced by pABA-dependent signaling, but virulence in a murine bone loss model is diminished. In contrast, interspecies coadhesion increases pathogenic potential in this model. Our data further suggest that that the synergistic pathogenicity of P. gingivalis-S. gordonii communities arises from upregulation of genes controlled by the RprY response regulator, including sufBCD which encode Fe-S clusters important in resistance to oxidative stress and oxidative killing in neutrophils.
The Aims of the project are thus to 1) Characterize the P. gingivalis tyrosine kinase/phosphatase signaling axis. In vitro and in vivo mutational approaches will be adopted to decipher the operational mode of the P. gingivalis tyrosine kinase Ptk1, and the molecular basis of control of signal transduction. 2) Characterize tyrosine cross- phosphorylation of the RprY response regulator in P. gingivalis. The functional consequences of tyrosine phosphorylation of RprY, and the integration of this response regulator into the streptococcal induced signaling hub, will be determined. 3) Determine the role of the Suf complex of P. gingivalis in polymicrobial synergy. The role of the RprY-controlled suf genes in mediating resistance to neutrophil killing and determining polymicrobial synergy in the murine alveolar bone loss model will be established. Successful completion of this project will provide fundamental novel information regarding the regulation of synergistic pathogenicity displayed by P. gingivalis and S. gordonii, which could ultimately be translated into therapeutic strategies designed to target the community-based pathogenesis that underlies periodontal disease.
Diseases caused by mixtures of bacteria are often more serious and harder to treat that those caused by a single organism. Periodontal (gum) diseases are caused by mixtures of organisms that communicate with each other to become more aggressive. In this proposal we shall study the communication mechanisms that allow groups of periodontal bacteria to increase in number and resist killing by the host.
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