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Institute of Dental ResearchWork at the Institute of Dental Research (IDR) focuses on common oral infections, including dental caries and periodontal disease, which have complex aetiologies.
Current research initiatives include:
Proteomics and structural genomics of oral pathogensThe difficulty in preventing dental caries results from the need to devise a strategy to eliminate key cariogenic species without disrupting the overall complexity of the protective biofilm community on teeth. Solving this problem is at the forefront of research at the IDR. The completion of a comprehensive series of comparative proteome studies, involving both planktonic and biofilm grown cells, has highlighted a number of biochemical events that are unique for the survival of the cariogenic pathogen, Streptococcus mutans, that proliferates under acidic conditions in dental plaque. Genes implicated in these adaptive responses, including alteration in acid tolerance and biofilm formation, are being systematically examined using a functional genomics approach. By defining the critical events associated with the survival and proliferation of S. mutans under conditions that lead to enamel dissolution, researchers at the IDR are gaining the necessary knowledge to develop a comprehensive strategy for intervention, thus allowing appropriate susceptible biochemical events to be targeted to control or eliminate disease.
Oral bacteria and infective endocarditisStreptococcus gordonii is a primary coloniser of oral microbial biofilms. This organism is considered to be beneficial in the oral environment but pathogenic when it colonises heart valves as this results in the disease, infective endocarditis, which has a high rate of morbidity. There is considerable interest in attempting to engineer this bacterium to be both non-pathogenic and to resist displacement by oral pathogens such as Streptococcus mutans. In vitro gene expression technology has identified the gom locus comprising a regulon of 15 open reading frames implicated in bacterial growth, beneficial adhesion to the tooth surface, and pathogenic colonisation of heart valves. Analysis of this locus by researchers at the IDR has focussed on a group of novel glycosidases within the gom locus with the 3D-structure of the first of these, GcnA, recently having being solved at high resolution. Current research is directed at the selective inhibition of this glycosidase as well as to determining the structure and function of other products of the gom locus including two related glycosidases that are also implicated in infective endocarditis.
Polymicrobial aetiology of caries progressionIn studies at the IDR using molecular phylogenetic techniques, some eighty bacterial species have been detected within the polymicrobial consortia of carious dentine following an extension of the enamel lesion of dental caries. Recent studies have shown that pulpal infection that arises from end-stage dentinal caries is far more selective. By using fluorescence in situ hybridisation (FISH), the complex consortia of bacteria associated with carious dentine has been shown to mass at the periphery of the soft tissue, with only a few species invading. Currently, the structural framework and spatial arrangement of bacterial invasion is being mapped. While clinically important from a dental perspective, this process also provides a rare insight into the dynamics of polymicrobial infections that impact severely on human health, particularly chronic infections.
Targeted control of oral pathogensCompetition for iron is considered to be a central event in many infections. A number of pathogenic bacteria have acquired complex mechanisms to sequester iron, often from haem. The periodontal pathogen, Porphyromonas gingivalis, is unusual in that it has lost the capacity to synthesise the porphyrin macrocycle and therefore must obtain this from tissue sources, usually from haem-proteins that may also supply iron. Research at the IDR has identified the so-called HA2 receptor as a porphyrin receptor important in the acquisition and surface storage of haem. This receptor mechanism has recently been used to selectively target and inhibit this bacterium with custom synthesised modified porphyrin-antibiotic conjugates. More recently, a number of other haem binding proteins that are located on the surface of the organism have been identified and are being studies in order to expand the range of targets for inhibition by exploiting aspects of porphyrin storage and transport that are unique to P. gingivalis.
Determinants of oral infection in high-risk Aboriginal communitiesAnaerobic Gram negative bacteria have been determined to be numerically important in relation to the early onset and high incidence of periodontal disease in an Aboriginal community. Research at the IDR has suggested that early mucosal colonisation of infants with pathogenic porphyromonads act as release sites for transmission of these organisms within families. Biotyping of Porphyromonas gingivalis strains based on variations in the lysine-gingipain gene indicated skewing of biotype distribution in the Aboriginal community compared with that observed in metropolitan cohorts. Further evidence for the presence of characteristic discriminatory flora within the Aboriginal community was obtained by microbial population analysis based on molecular phylogeny. These observations have provided a basis for ongoing dissection of the microbial risk factors for oral infection that prevail in such a high risk group and underpin proposed strategies to break the cycle of disease by preventing transmission to infants. Additionally, there is no information to determine whether disease susceptibility amongst Aborigines reflects organisms that have been associated with Aboriginal people for millennia or if there is a pathogenic influence from organisms acquired, most probably, from Anglo-Saxon settlers. As there is little genomic information for these mucosal pathogens, assessment of the origin and heterogeneity of organisms within communities is being assessed by analysis of a matrix of highly conserved house-keeping genes. This will both establish the relative diversity of strains of the organism within the community and also probe the question of separation or overlap with similarly studied organisms from Anglo-Saxon sources, with isolates from other ethnic groups providing outlier controls.
Role of oral bacteria in immune development in marsupialsAt birth, the highly under-developed Tammar wallaby, Macropus eugenii, climbs through a saliva coated channel in the fur of its mother from the urogenital tract to the pouch which has also been cleaned by the licking action of the mother. For the first three months of its development the neonate is attached to a teat in the pouch and is totally dependent on its surrounding environment for immunological protection since it does not possess mature lymphoid tissue and therefore lacks immune competence. It is well recognized in eutherian mammals that bacteria play a pivotal role in maintaining the health of mucosal surfaces and in aiding immune development. While preliminary studies have shown that the bacterial microflora of the Tammar wallaby pouch young changes with time, the exact nature of these microbial changes, has not been elucidated. In collaboration with Macquarie University, researchers at the IDR are engaged in using advanced molecular phylogenetic methods to identify those bacteria that are transmitted to the neonate and the role oral bacteria play in both protecting the neonate from infection and in influencing mucosal development and maturation of the immune system.
ContactsDirector Institute of Dental Research T +61 2 9845 8762 F + 61 2 9845 7599
Principal Research Scientist T +61 2 9845 8763 F +61 2 9845 7599 E njacques@dental.wsahs.nsw.gov.au
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