The predominant polymicrobic infection of mankind is expressed clinically as periodontal disease, which afflicts nearly one-half of the population by 50 years of age, and is related to development of a microbial biofilm colonizing the subgingival sulcus. The suggested mechanisms of pathogenesis are varied, in most part due to the complex microbial community consisting of numerous bacterial taxa, viruses, and fungi. Nevertheless, certain of these subgingival microbial consortia are consistently correlated with a progressive destruction of sot_ and hard tissue that have been well documented to occur in clinical settings (i.e., periodontitis). Various in vivo and in vitro investigations have suggested that the dominance of selected species in the subgingival ecology results from both microbial synergistic and antagonistic relationships. These have been linked to the nature of available surfaces for colonization, available nutrients, and physiologic """"""""food webs"""""""" that exists within the community. Molecular microbiologic studies have described nearly 500 species of bacteria that can inhabit this ecological niche, although several specific microbial complexes have been described at sites of progressing tissue destruction. A predominant consortia identified in a majority of adult periodontitis patients consists of Porphyromonas gingivalis, TannereIla forsythensis [Bacteroides forsythus], and Treponema denticola. The correlation of this consortium with disease has been proposed to result from synergistic physiological, host evasion, and/or tissue destructive capabilities among the component species. The objectives of this R01 application are to test a hypothesis that this polymicrobic consortium comprises a """"""""virulence web"""""""" that synergistically increases tissue destructive host responses, and the consortia to be less effective modify that host immune responses.
Three Specific Aims are proposed using an animal model system to test this hypothesis: (1) To determine molecular interbacterial synergistic virulence effects of P. gingivalis, T. forsythensis, and T denticola in an in vivo calvarial bone resorption model, (2) To determine the characteristics of acquired humoral immune responses to a polymicrobial infection and the ability of this response to modulate in vivo calvarial bone resorption, and (3) To determine the characteristics of active humoral immune responses to polymicrobial immunization and ability of this response to modulate bone resorption. The long-range goals from this study will be to document microbial interactions, virulence synergisms, characterize both acquired and active immune responses, and relate these to alterations in tissue destruction and bone resorption. The significance of this application is that clinical observations have shown the ability of oral microorganisms to translocate into the circulation and manifest systemically as endocarditis, brain/kidney/lung, and intra-abdominal infections and contributing to risks of diabetes, coronary artery disease, osteoporosis, obesity, and preterm birth. Consequently, the host response to these chronic infections must be considered as critical to general health.
