Aggregatibacter actinomycetemcomitans (Aa) is a key pathogen in the polymicrobial infection of periodontitis. Colonization by distinct clonal lineages of Aa may lead to different consequences, from minimal diseases to the development of aggressive periodontitis. The basis for the variable virulence of Aa is not fully understood, an presents a challenge to effective diagnosis and management of Aa-associated periodontitis. Aa demonstrates significant variation in gene content primarily because of genomic islands, which have been known to be associated with bacterial virulence potential. The long-term goal of our research plan is to identify the full spectrum of the virulence determinants of Aa. Toward that goal, the objective of this study is to define the role of genomic islands in the pathogenesis of A in periodontitis. The central hypothesis is that the virulence of Aa is modulated by genomic islands and mediated by Th17 cells and counteracted by Treg. The hypothesis is formulated based on the preliminary studies of the 171 Aa genomic islands that demonstrated (i) disease-association of specific island genes, (ii) distribution of some island genes limited to Aa strains f high virulence, (iii) homology of individual island genes to known virulence factors of other pathogens, and (iv) patterns of expression of the island genes that suggested functionality.
Two aims will be pursued:
Aim 1. In vitro functional analysis of genomic islands of Aa. The working hypothesis is that genomic islands are expressed in in vivo like conditions and modulate the virulence expression of Aa.
Aim 2. In vivo characterization of the role of genomic islands to Aa virulence. The working hypothesis is that the genomic islands modulate the virulence of Aa in periodontitis via Th17 and regulatory T cell immune responses;the former leads to osteolysis and tissue destruction, while the latter dampens the inflammatory response. The hypothesis will be tested with a novel animal model of rats. The outlined studies will for the first time evaluate and identify virulence-associated genomic islands of Aa and reveal their pathogenic mechanisms. The results are expected to have an important positive impact, because the information will expand the knowledge to the pathogenesis of Aa leading to improved diagnostics and treatment of periodontal infections.

Public Health Relevance

The proposed research is relevant to the NIDCR's mission "to improve oral health...through research..." because A. actinomycetemcomitans (Aa) is a major etiology of periodontitis. Our long-term goal is to identify the full spectrum of the virulene determinants of Aa. The results will lead to improved diagnostics and treatment of the disease. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE012212-11A1
Application #
8371620
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Lunsford, Dwayne
Project Start
1999-01-01
Project End
2017-06-30
Budget Start
2012-07-12
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$432,874
Indirect Cost
$127,117
Name
University of Southern California
Department
Dentistry
Type
Schools of Dentistry
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Ando-Suguimoto, Ellen Sayuri; da Silva, Maike Paulino; Kawamoto, Dione et al. (2014) The cytolethal distending toxin of Aggregatibacter actinomycetemcomitans inhibits macrophage phagocytosis and subverts cytokine production. Cytokine 66:46-53
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Brinkman, Cassandra L; Bumgarner, Roger; Kittichotirat, Weerayuth et al. (2013) Characterization of the effects of an rpoC mutation that confers resistance to the Fst peptide toxin-antitoxin system toxin. J Bacteriol 195:156-66
Chen, Casey; Kittichotirat, Weerayuth; Chen, Weizhen et al. (2012) Genome sequence of a serotype b non-JP2 aggregatibacter actinomycetemcomitans strain, ANH9381, from a periodontally healthy individual. J Bacteriol 194:1837
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Butler-Wu, Susan M; Sengupta, Dhruba J; Kittichotirat, Weerayuth et al. (2011) Genome sequence of a novel species, Propionibacterium humerusii. J Bacteriol 193:3678
Kittichotirat, Weerayuth; Bumgarner, Roger E; Asikainen, Sirkka et al. (2011) Identification of the pangenome and its components in 14 distinct Aggregatibacter actinomycetemcomitans strains by comparative genomic analysis. PLoS One 6:e22420
Kittichotirat, Weerayuth; Bumgarner, Roger; Chen, Casey (2010) Markedly different genome arrangements between serotype a strains and serotypes b or c strains of Aggregatibacter actinomycetemcomitans. BMC Genomics 11:489

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