Senior Member of the Staff
Department of Immunology
Associate Clinical Professor
Department of Oral Medicine, Infection and Immunity
Harvard School of Dental Medicine
email:
Houghton College, B.S., 1966, General Science
New York Medical College, Ph.D., 1972, Immunochemistry
The outstanding success of vaccines in combating infectious diseases is now a familiar story. The Smith lab uses vaccines as a strategy to prevent some of the most common of all human infections, those leading to tooth decay. We study how and when young children acquire these infections and how a child's developing immune system normally responds to them. Using this knowledge, we are designing vaccines to block potentially harmful infections before they can initiate disease. We also investigate ways to produce and administer vaccines to optimize their effectiveness and ways to boost natural immune responses in order to induce protective immunity in locations where it will be most beneficial.
The infant immune system is confronted with an increasingly complex set of infectious challenges by commensal and pathogenic microorganisms. Researchers in the Smith laboratory seek to understand the interplay between colonization of the oral cavity and maturation of the secretory immune system. We are defining the characteristics of salivary antibody developed in response to antigenic challenges by commensal bacteria during the first years of life.
An important goal of our work is the design of mucosal vaccines to interfere with colonization by pathogenic oral flora before potentially cariogenic infections can become established. Because mutans streptococci are often the primary etiological agents of dental caries, we are identifying potential virulence antigens in these organisms that may be good candidates for vaccines. We have shown that mutans streptococcal infections are initiated in children between 18 to 36 months of age. Immunization before this time may therefore be most effective in prevention. Natural salivary immune responses to mutans streptococcal antigens are being examined to define the breadth of immune coverage necessary for effective vaccines.
Dental caries results from the dissolution of mineral in the enamel and dentin of the tooth by organic acids secreted by certain dental plaque microbiota. Accumulation of cariogenic streptococci is mediated by the activity of extracellular glucosyltransferases (GTFs) that utilize sucrose to synthesize high molecular weight branched extracellular polysaccharides. We have shown the effectiveness of mutans streptococcal GTF immunogens in inhibiting dental caries in a rodent model of disease and in modifying mutans streptococcal accumulation in human clinical trials.
The molecular pathogenesis of mutans streptococci involves binding of GTF-synthesized glucans to the bacterial cell surface via glucan-binding proteins (GBP). We have identified several apparently important S. mutans and S. sobrinus GbpBs At least one of these putative virulence components, GbpB, appears to be sufficiently immunogenic in humans to merit investigation for use in a dental caries vaccine. We recently cloned and sequenced the GbpB gene, and showed that active immunization with GbpB or passive immunization with IgY antibody to GbpB results in protection in rodent caries models. We are currently exploring functional characteristics of GbpB. Concurrently human monoclonal antibodies to Gtf epitopes are being identified and evaluated boy in vitro and in vivo.
The expression characteristics of GTF and Gbp components may ultimately influence the ability of cariogenic streptococci to cause disease. Young children with high environmental risk for infection who are initially colonized with strains of S. mutans with lower GTF activity have lower caries risk. Using strains isolated from these children, we are exploring the relationship between the expression of these virulence components at the genetic and protein levels and the behavior of these strains in bacterial biofilms. We are also dissecting the epitopes of the natural immune responses to GTF and Gbp in the salivas of children during the intital stages of S. mutans colonization. Regulation of virulence antigen expression is also being studied.
Another focus of research is aimed at improving the amount and duration of secretion of salivary IgA antibody to oral pathogens. Inductive sites for mucosal immunity in the head and neck region, including nasal-associated lymphoid tissue (NALT), the tonsils, the minor salivary gland (MSG) network, as well as other, more distant inductive sites, are under evaluation for their usefulness as routes for delivery of vaccines that target oral pathogens. We are also exploring novel delivery vehicles and biological adjuvants, applied together with antigen at these sites, for their ability to enhance mucosal immunity in the oral cavity and in secretions at other mucosal sites.
Nogueira RD, King WF, Gunda G, Culshaw S, Taubman MA, Mattos-Graner RO, Smith DJ. (2008) Mutans streptococcal infection induces salivary antibody to virulence proteins and associated functional domains. Infect. Immun. 76:3606-3613.
Stipp RN, Gonçalves RB, Höfling JF, Smith DJ, Mattos-Graner RO. (2008) Transcriptional analysis of gtfB, gtfC, and gbpB and their putative response regulators in several isolates of Streptococcus mutans. Oral Microbiol. Immunol. 23:466-473.
Smith DJ, Mattos-Graner RO. (2008) Secretory immunity following mutans streptococcal infection or immunization. Curr. Top. Microbiol. Immunol. 319:131-156.
Harada Y, Han X, Yamashita K, Kawai T, Eastcott JW, Smith DJ, Taubman MA. (2006) Effect of adoptive transfer of antigen-specific B cells on periodontal bone resorption. J. Periodontal Res. 41(2):101-107.
Mattos-Graner RO, Porter KA, Smith DJ, Hosogi Y, Duncan MJ. (2006) Functional analysis of glucan binding protein B from Streptococcus mutans. J. Bacteriol. 188(11):3813–3825.
Klein MI, Bang S, Florio FM, Holfing JF, Goncalves RB, Smith DJ, MattosGraner RO. (2006) Genetic diversity of competence gene loci in clinical genotypes of Streptococcus mutans. J. Clin. Microbiol. 44(8):3015-3020.
Smith DJ, King WF, Rivero J, Taubman MA. (2005) Immunological and protective effects of diepitopic subunit dental caries vaccines. Infect. Immun. 73(5):2797-2804.
Nogueira RD, Alves AC, Napimoga MH, Smith DJ, Mattos-Graner RO. *(2005) Characterization of salivary immunoglobulin A responses in children heavily exposed to the oral bacterium Streptococcus mutans: Influence of specific antigen recognition in infection. Infect. Immun. 73(9) :5675-5684.
Peacock ZS, Barnes LA, King WF, Trantolo DJ, Wise DL, Taubman MA, Smith DJ. (2005) Influence of micro-particle formulation on immunogenicity of SYI, a synthetic peptide derived from Streptococcus mutans GbpB. Oral Microbiol. Immunol. 20(1):60-64.
Bill King
Thias Parisotto
Nicole Juskiw
Cecelia Kolstad
