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Exotoxins of Aggregatibacter actinomycetemcomitans and periodontal attachment loss in adolescents
Umeå University, Faculty of Medicine, Department of Odontology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Aggregatibacter actinomycetemcomitans is an oral bacterium that is mainly associated with aggressive forms of periodontitis, which most often starts at an early age. Amongst the virulence factors of A. actinomycetemcomitans, two exotoxins, the leukotoxin (LtxA) and the cytolethal distending toxin (Cdt), are suggested to play an important role in the pathogenicity of aggressive periodontitis. There is also a genetic diversity of the different strains of A. actinomycetemcomitans, and a variation in the ability of different strains to express and release exotoxins has been suggested. Of the different genotypes of A. actinomycetemcomitans, the highly leukotoxic JP2 genotype, which is prevalent in individuals of African origin, seems to be the genotype that is most strongly associated with localized aggressive periodontitis.

This thesis is built upon studies of a West African adolescent population. The aim was to study the virulence characteristics of A. actinomycetemcomitans genotypes with a specific focus on the LtxA and the Cdt in relation to the progression of attachment loss (AL). The specific aim was first, to investigate cross-sectionally the presence of the JP2 and non-JP2 genotypes of A. actinomycetemcomitans in relation to the prevalence of AL and then prospectively to assess the progression of AL in a Ghanaian adolescent population. Second, in clinical isolates of A. actinomycetemcomitans obtained from the participants of the study, the serotypes and the virulence characteristics related to the two exotoxins were studied and associated with the progression of AL at the individual level.

In Paper I, based on the study population consisting of 500 adolescents (mean age 13.2 years; SD ±1.5), it was shown that the overall carrier rate of A. actinomycetemcomitans was high (54.4%) and that the presence of this bacterium was associated with AL ≥ 3 mm. The JP2 genotype was prevalent (8.8%) in this population. In Paper II, 397 (79.4%) of the study participants were periodontally examined again at a 2-year follow-up. The presence of the JP2 genotype of A. actinomycetemcomitans in subgingival plaque was strongly associated with the progression of AL. This study also provided support for an enhanced estimated risk (odds ratio, OR=3.4), though less pronounced, for the progression of AL in individuals positive for the non-JP2 genotypes of A. actinomycetemcomitans.

In Paper III, all three cdt genes (a, b and c) were detected in 79% of the examined A. actinomycetemcomitans isolates, all of which expressed an active toxin. The distribution of the cdt genes showed a serotype-dependent pattern. In particular, the presence of the b serotypes (both JP2 and non-JP2 genotypes) was associated with the disease progression, whereas the expression of Cdt was not particularly related to the disease progression.  In Paper IV, it was shown that the presence of of A. actinomycetemcomitans isolates with high leukotoxicity, also those of the non-JP2 genotypes of A. actinomycetemcomitans, were associated with an increased risk of the progression of AL in relation to the reference group. The main proportion of the serotype b isolates was distributed in the category of highly leukotoxic isolates. The analyses of the non-JP2 genotypes of serotype b indicated a diversity linked to the level of leukotoxicity.

In conclusion, A. actinomycetemcomitans in general was associated with the progression of AL. Individuals with an increased risk of developing progression of AL mainly harboured isolates of A. actinomycetemcomitans with a high leukotoxicity, which suggests that the LtxA is an important virulence factor. Of the two exotoxins, the pathogenic potential was mainly associated with the LtxA, while the role of the Cdt is unclear.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2013. , 87 p.
Series
Umeå University odontological dissertations, ISSN 0345-7532 ; 131
Keyword [en]
Aggregatibacter actinomycetemcomitans, periodontal attachment loss, JP2 genotype, non-JP2 genotype, LtxA, Cdt
National Category
Dentistry
Research subject
Infectious Diseases
Identifiers
URN: urn:nbn:se:umu:diva-83986ISBN: 978-91-7459-787-5 (print)OAI: oai:DiVA.org:umu-83986DiVA: diva2:678416
Public defence
2014-01-31, Hörsal Betula, Unod L, plan 0, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council, 396022002
Available from: 2013-12-18 Created: 2013-12-12 Last updated: 2013-12-18Bibliographically approved
List of papers
1. Presence of JP2 and Non-JP2 genotypes of aggregatibacter actinomycetemcomitans and periodontal attachment loss in adolescents in Ghana
Open this publication in new window or tab >>Presence of JP2 and Non-JP2 genotypes of aggregatibacter actinomycetemcomitans and periodontal attachment loss in adolescents in Ghana
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2012 (English)In: Journal of Periodontology, ISSN 0022-3492, E-ISSN 1943-3670, Vol. 83, no 12, 1520-1528 p.Article in journal (Refereed) Published
Abstract [en]

Background: Limited data are reported concerning the presence of A. actinomycetemcomitans and attachment loss (AL) in sub-Saharan countries. The authors investigate the carrier frequency of JP2 and non-JP2 genotypes of A. actinomycetemcomitans and the presence of AL in Ghanaian adolescents and evaluate socioeconomic conditions and oral hygiene practices. Methods: Five hundred individuals (mean +/- SD age: 13.2 +/- 1.5 years) in public and private schools were interviewed about demographic characteristics and oral hygiene practices and were given a full-mouth periodontal examination. Subgingival plaque samples were obtained from periodontal sites around permanent first molars and incisors. The carrier status of A. actinomycetemcomitans at the individual level was determined based on results obtained by cultivation and polymerase chain reaction. Results: The findings of this study show a relatively high carrier rate of JP2 and non-JP2 genotypes of Aggregatibacter actinomycetemcomitans in the Ghanaian adolescent population and the presence of this bacterium is associated with the occurrence of AL. The overall carrier rate of A. actinomycetemcomitans was 54.4%, and the highly leukotoxic JP2 genotype was detected in 8.8% of the study population. A total of 107 (21.4%) individuals had >= 1 tooth with AL >= 3 mm. The majority of the individuals carrying A. actinomycetemcomitans (80.1%) (P<0.001) and of the periodontally diseased individuals (91.6%) (P<0.001) were found in public schools. Conclusions: A. actinomycetemcomitans and AL were frequently found in Ghanaian adolescents. The school type was the strongest predictor of both presence of A. actinomycetemcomitans and AL.

Place, publisher, year, edition, pages
American Academy of Periodontology, 2012
Keyword
adolescent, Africa South of the Sahara, epidemiology, microbiology, periodontal attachment loss, periodontitis
National Category
Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-53226 (URN)10.1902/jop.2012.110699 (DOI)000312355600011 ()22376208 (PubMedID)
Available from: 2012-04-14 Created: 2012-03-18 Last updated: 2017-12-07Bibliographically approved
2. Progression of attachment loss is strongly associated with presence of the JP2 genotype of Aggregatibacter actinomycetemcomitans: a prospective cohort study of a young adolescent population
Open this publication in new window or tab >>Progression of attachment loss is strongly associated with presence of the JP2 genotype of Aggregatibacter actinomycetemcomitans: a prospective cohort study of a young adolescent population
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2014 (English)In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 41, no 3, 232-241 p.Article in journal (Refereed) Published
Abstract [en]

AIM: To assess the progression of attachment loss (AL) during a two-year period according to the presence of JP2 and non-JP2 genotypes of A. actinomycetemcomitans in a Ghanaian adolescent population.

METHODS: A total of 500 adolescents (mean age 13.2 years, SD± 1.5) were enrolled in the study. After two years, 397 (79.4%) returned for a periodontal re-examination, including the measurement of AL. The carrier status of the JP2 and non-JP2 genotypes of A. actinomycetemcomitans was evaluated in a baseline examination two years earlier.

RESULTS: Individuals who carried the JP2 genotype of A. actinomycetemcomitans had a significantly increased risk (relative risk (RR) = 7.3) of developing AL ≥ 3 mm. The mean AL at the follow-up and the mean two-year progression of AL was significantly higher in the JP2 genotype-positive group (n=38) compared with the group positive for the non-JP2 genotypes of A. actinomycetemcomitans (n=169), and the group of A. actinomycetemcomitans-negative individuals (n=190). The JP2 genotype was strongly associated with the progression of AL ≥ 3 mm (OR= 14.3). The non-JP2 genotypes of A. actinomycetemcomitans were also, however less pronounced, associated with the progression of AL ≥ 3 mm (OR=3.4).

CONCLUSION: The JP2 genotype of A. actinomycetemcomitans is strongly associated with the progression of AL.

Keyword
A. actinomycetemcomitans, JP2 genotype, attachment loss, progression, leukotoxin, Ghana, periodontitis, adolescent
National Category
Dentistry
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:umu:diva-83805 (URN)10.1111/jcpe.12209 (DOI)000330577300003 ()24304011 (PubMedID)
Funder
Swedish Research Council
Available from: 2013-12-08 Created: 2013-12-07 Last updated: 2017-12-06Bibliographically approved
3. Cytolethal distending toxin in isolates of Aggregatibacter actinomycetemcomitans from Ghanaian adolescents and association with serotype and disease progression
Open this publication in new window or tab >>Cytolethal distending toxin in isolates of Aggregatibacter actinomycetemcomitans from Ghanaian adolescents and association with serotype and disease progression
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, e65781- p.Article in journal (Refereed) Published
Abstract [en]

Background and Objectives: The cytolethal distending toxin (Cdt) is a highly conserved exotoxin that are produced by a number of Gram negative bacteria, including Aggregatibacter actinomycetemcomitans, and affects mammalian cells by inhibiting cell division and causing apoptosis. A complete cdt-operon is present in the majority of A. actinomycetemcomitans, but the proportion of isolates that lack cdt-encoding genes (A, B and C) varies according to the population studied. The objectives of this study were to examine serotype, Cdt-genotype, and Cdt-activity in isolates of A. actinomycetemcomitans collected from an adolescent West African population and to examine the association between the carrier status of A. actinomycetemcomitans and the progression of attachment loss (AL).

Material and Methods: A total of 249 A. actinomycetemcomitans isolates from 200 Ghanaian adolescents were examined for serotype and cdt-genotype by PCR. The activity of the Cdt-toxin was examined by DNA-staining of exposed cultured cells and documented with flow cytometry. The periodontal status of the participants was examined at baseline and at a two-year follow-up.

Results: Presence of all three cdt-encoding genes was detected in 79% of the examined A. actinomycetemcomitans isolates. All these isolates showed a substantial Cdt-activity. The two different cdt-genotypes (with and without presence of all three cdt-encoding genes) showed a serotype-dependent distribution pattern. Presence of A. actinomycetemcomitans was significantly associated with progression of AL (OR = 5.126; 95% CI = [2.994 - 8.779], p < 0.001).

Conclusion: A. actinomycetemcomitans isolated from the Ghanaian adolescents showed a distribution of serotype and cdt-genotype in line with results based on other previously studied populations. Presence of A. actinomycetemcomitans was significantly associated with disease progression, in particular the b serotype, whereas the association with disease progression was not particularly related to cdt-genotype, and Cdt-activity.

Place, publisher, year, edition, pages
Public Library Science, 2013
Keyword
Aggregatibacter actinomycetemcomitans, cytolethal distending toxin (Cdt), attachment loss (AL)
National Category
Dentistry
Research subject
Microbiology
Identifiers
urn:nbn:se:umu:diva-73249 (URN)10.1371/journal.pone.0065781 (DOI)000320363300043 ()23922633 (PubMedID)
Available from: 2013-06-19 Created: 2013-06-19 Last updated: 2017-12-06Bibliographically approved
4. Leukotoxic activity of Aggregatibacter actinomycetemcomitans and periodontal attachment loss
Open this publication in new window or tab >>Leukotoxic activity of Aggregatibacter actinomycetemcomitans and periodontal attachment loss
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 8, e104095- p.Article in journal (Refereed) Published
Abstract [en]

Aggregatibacter actinomycetemcomitans is a Gram-negative periodontitis-associated bacterium that expresses a toxin that selectively affects leukocytes. This leukotoxin is encoded by an operon belonging to the core genome of this bacterial species. Variations in the expression of the leukotoxin have been reported, and a well-characterized specific clonal type (JP2) of this bacterium with enhanced leukotoxin expression has been isolated. In particular, the presence of the JP2 genotype significantly increases the risk for the progression of periodontal attachment loss (AL). Based on these findings we hypothesized that variations in the leukotoxicity are linked to disease progression in infected individuals. In the present study, the leukotoxicity of 239 clinical isolates of A. actinomycetemcomitans was analysed with different bioassays, and the genetic peculiarities of the isolates were related to their leukotoxicity based on examination with molecular techniques. The periodontal status of the individuals sampled for the presence of A. actinomycetemcomitans was examined longitudinally, and the importance of the observed variations in leukotoxicity was evaluated in relation to disease progression. Our data show that high leukotoxicity correlates with an enhanced risk for the progression of AL. The JP2 genotype isolates were all highly leukotoxic, while the isolates with an intact leukotoxin promoter (non-JP2 genotypes) showed substantial variation in leukotoxicity. Genetic characterization of the non-JP2 genotype isolates indicated the presence of highly leukotoxic genotypes of serotype b with similarities to the JP2 genotype. Based on these results, we conclude that A. actinomycetemcomitans harbours other highly virulent genotypes besides the previously described JP2 genotype. In addition, the results from the present study further highlight the importance of the leukotoxin as a key virulence factor in aggressive forms of periodontitis.

Place, publisher, year, edition, pages
Public library science, 2014
Keyword
Aggregatibacter actinomycetemcomitans, leukotoxin (ltxA), periodontitis, attachment loss (AL)
National Category
Dentistry
Research subject
Odontology
Identifiers
urn:nbn:se:umu:diva-84192 (URN)10.1371/journal.pone.0104095 (DOI)000341357200065 ()25093857 (PubMedID)
Funder
Swedish Research Council
Note

Published in thesis in manuscript form with the title: Leukotoxic activity of Aggregatibacter actinomycetemcomitans.

Available from: 2013-12-17 Created: 2013-12-17 Last updated: 2017-12-06Bibliographically approved

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