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The viridans group streptococci generally co-exist with the host as benign, commensal microorganisms in the oral cavity and on mucosal surfaces, but their thrombogenic potential, for example, is expressed when they are inoculated into the circulation. We seek to define the mechanisms that enable viridans streptococci to assume dichotomous roles in health and disease.

How do these streptococci attach to the teeth and colonize? Using anti-idiotypic monoclonal antibodies, we have shown that bimolecular protein complexes are probably expressed on the salivary film [pellicle] that coats the teeth. These complexes appear to serve as receptors for certain viridans streptococci. Most of these streptococci will colonize the tooth, but cause no apparent disease in the mouth or the gastrointestinal tract.

Why do these streptococci cause endocarditis? When these streptococci enter the blood, they show special potential to cause disease. We have shown that the thrombogenic potential of these streptococci is expressed on a cell wall protein with a structural motif common in platelet-interactive domains of collagen. This motif explains, at least in part, the thrombogenic role of viridans streptococci in experimental endocarditis.

In the blood, can these streptococci cause other problems? Possibly yes. Acute myocardial infarctions are often caused by thromboembolic blockage of coronary arteries. Recent epidemiological studies show that an important risk factor for myocardial infarction is periodontal disease [gum infections]. The viridans streptococci are the most abundant microorganisms in dental plaque and frequently appear in the blood during periodontal disease. We have shown that thrombogenic viridans streptococci may cause myocardial infarction in experimental animals.

How does the gingival epithelium protect against microbial invasion? Many microorganisms that colonize the oral cavity have the potential to invade the gingival epithelium and perhaps gain entry into the circulation. Yet microorganisms are rarely found inside of mucosal epithelial cells. We have shown that gingival epithelial cells synthesize and express the antimicrobial protein, calprotectin. During periodontitis or other oral infections, calprotectin in the gingiva appears to be upregulated. It is likely, therefore, that upregulation of calprotectin is a response designed to protect the epithelium against the threat of invading microorganisms. Leukocytes also protect against microorganisms that have breached the epithelium. We have shown that nicotine from cigarette smoking can inhibit the antimicrobial functions of polymorphonuclear leukocytes, increasing the risk of periodontal disease.

Do these streptococci serve a useful purpose? The commensal viridans streptococci colonize the teeth during infancy. In the perinatal period, these streptococci first encounter the mucosal immune system. When processed transmucosally, the collagen-like streptococcal motif [domain] may also regulate tolerance to the host protein, collagen. The toleragenic domain of type II collagen and the streptococcal motif are remarkably similar and so protection may occur against autoimmune diseases, such as arthritis. In genetically at-risk individuals, the systemic immune system reacts to collagen. Acquisition of streptococci expressing this structural motif may, therefore, regulate the susceptibility to arthritis.

Ongoing studies. Studies of (1) molecular mechanisms in the pathophysiology of S. sanguis endocarditis; (2) anti-idiotypic antibody probes of host receptors for S. sanguis; (3) mucosal epithelial calprotectin as a defense against invading bacteria; and (4) S. sanguis modulation of tolerance in murine arthritis.

MacFarlane, G.D., Herzberg, M.C., Wolff, L.F. & Hardie, N.A. Refractory periodontitis associated with abnormal polymorphonuclear leukocyte phagocytosis and cigarette smoking. J Periodontol 63: 908-913, 1992.

Stoltenberg, J.L., Osborn, J.B., Pihlstrom, B.L., Herzberg, M.C., Aeppli, D.M., Wolff, L.F. & Fischer, G.E.Association between cigarette smoking, bacterial pathogens, and periodontal status. J. Periodontol 64:1225-1330, 1993.

Herzberg, M.C ., Krishnan, L. K. & MacFarlane, G .D. Involvement of alpha2-adenoreceptors and G-proteins in the modulation of platelet secretion in response to Streptococcus sanguis. Crit Rev Oral Biol 4:435-442, 1993.

Govze, Y. & Herzberg, M.C. Serum and gingival crevicular fluid anti-desmosomal antibodies in periodontitis. J Periodontol 64:603-608, 1993.

Erickson, P.R. & Herzberg, M.C. The Streptococcus sanguis platelet aggregation-associated protein: Identification and characterization of the minimal platelet interactive domain. J Biol Chem 268:1646-1649, 1993.

Erickson, PR & Herzberg, MC. Evidence for the covalent linkage of carbohydrate polymers to a glycoprotein from Streptococcus sanguis. J Biol Chem 268: 23780-23783, 1993.

MacFarlane, G.D., Sampson, D.E., Clawson, D.J., Clawson, C.C., Kelly, K.L. & Herzberg, M.C. Evidence for an ecto ATPase on the cell wall of Streptococcus sanguis. Oral Microbiol Immunol 2:180-185, 1994.

Seow, W.K., Thong, Y.H., Nelson, R.D., MacFarlane, G.D. & Herzberg, M.C. Nicotine-induced release of elastase and eicosanoids by human neutrophils. Inflammation 18: 119-127,1994.

Herzberg, M.C., MacFarlane, G.D., Liu, P. & Erickson, P.R. The platelet as an inflammatory cell in periodontal diseases. In: Molecular Pathogenesis of Periodontal Disease. R.J. Genco, et al. (Eds.), Amer Soc Microbiol, Washington, D.C., 247 255, 1994.

Meyer, M.W., Witt, A.R., Krishnan, L.K., Yokota, M.J. Rudney, J.D. & Herzberg, M.C. Therapeutic advantage of recombinant human plasminogen activator in endocarditis: Evidence from experimental rabbits. Thromb Haemost 73: 680-682, 1995.

Erickson, P.R. & Herzberg, M.C. Altered expression of the platelet aggregation-associated protein (PAAP) from Streptococcus sanguis after growth in the presence of collagen. Infect Immun 63:1084-1088, 1995.

Gong, K., Wen, D.Y., Ouyang, T., Rao, A.T. & Herzberg, M.C. Platelet receptors for the Streptococcus sanguis adhesin and aggregation-associated antigens are distinguished by anti-idiotypical monoclonal antibodies. Infect Immun 63:3628 3633, 1995.