The highly leukotoxic JP2 clone of Aggregatibacter actinomycetemcomitans: evolutionary aspects, epidemiology and etiological role in aggressive periodontitis

Abstract

For many years, attention has been given to the oral bacterium Aggregatibacter actinomycetemcomitans, as a species possibly implicated in the etiology of aggressive periodontitis in adolescents. One of the major virulence factors of A. actinomycetemcomitans is the leukotoxin which is able to kill important cells of the immune system. As demonstrated in population genetic analyses, the population structure of A. actinomycetemcomitans is mainly clonal with evolutionary lineages corresponding to the serotypes. A particular highly leukotoxic clone (JP2) of serotype b has been discovered. The JP2 clone, with an estimated origin some 2400 years ago, is found to be highly conserved, based on analyses of a collection of JP2 clone strains collected through more than 20 years from individuals of diverse origin and living geographically widespread. Despite demonstration of minor evolutionary changes within the genome of JP2 clone strains of A. actinomycetemcomitans, the JP2 clone strains constitute a unique clonal type, the characteristics of which include a 530 basepair deletion in the leukotoxin operon implicated in the enhanced leukotoxic activity of the clone. Mapping of the geographic occurrence of the JP2 clone of A. actinomycetemcomitans has revealed that its colonization is largely restricted to individuals of African descent. Characteristic mutations, which allow JP2 clone isolates from the Mediterranean region to be distinguished from isolates from West Africa, including the Cape Verde islands, suggest that the JP2 clone initially emerged as a distinct genotype in the Mediterranean region of Africa and subsequently spread to West Africa, from where it might have been transferred to the American continent during the transatlantic slave trade. The finding of a sustained selective colonization of individuals of African descent, despite geographical separation from the African continent for centuries, suggests that the JP2 clone might have a distinct host tropism. Further studies are needed to elucidate the reasons for the apparent selective colonization of the Mediterranean and Western African populations. The JP2 clone of A. actinomycetemcomitans appears to play a prominent role in the etiology of aggressive periodontitis compared to other clonal types of the species. While A. actinomycetemcomitans, in general, is considered an opportunistic pathogen of the resident oral microbiota, the JP2 clone has features similar to those of an exogenous pathogen. Clonal types other than JP2 can be isolated from healthy as well as periodontally diseased individuals, whereas the JP2 clone has been isolated primarily from periodontally diseased individuals. As demonstrated in a prospective cohort study in Morocco, where the JP2 clone is endemically present, the presence of this clone in dental plaque confers a remarkably increased risk for development of aggressive periodontitis, suggesting that the JP2 clone is an important etiological agent of aggressive periodontitis in adolescents. Support for association of clonal types other...

Clinical and Microbiological Characterization of Patients with Generalized Aggressive Periodontitis

“…In concordance, this study demonstrated that the presence of A. actinomycetemcomitans was 32.5%. Similar to P. gingivalis, this microorganism also showed statistical association with higher PD, CAL and BOP, corroborating the results of Takeuchi et al At this time, A. actinomycetemcomitans is mostly viewed as opportunistic bacteria of the resident oral microbiota, while its specific JP2 clone, representing serotype b, has properties of a true exogenous pathogen (Haubek, 2010).…”

Virulence Mechanisms of Leukotoxin from Aggregatibacter actinomycetemcomitans

“…Unfortunately there is no animal model available for studying the virulence mechanisms of leukotoxin because of its specificity against defense cells of human or old world monkey origin. However, the strong correlation between presence of highly leukotoxic (JP2-clone) A. actinomycetemcomitans and development of attachment loss in adolescents indicates an important role of leukotoxin in the pathogenesis of aggressive periodontitis (Haubek, 2010). …”

“…Clonal diversity analysis of JP2-like isolates have shown that all strains of this clone have a common ancestor from Northern Africa (Haubek et al, 2007). The high accumulation of this clone in subjects of African origin has indicated a possible host tropism, but could also be a result of the strict vertical transmission pattern of this bacterium Haubek 2010). The expression of leukotoxin is also regulated by environmental factors, such as growth conditions and substrates (Kachlany et al, 2010).…”

“…The cellular and molecular mechanisms in which a modified leukotoxin promoter enhances the expression of leukotoxin are not known. The most well known phenomenon is the highly leukotoxic JP2 clonal strains of A. actinomycetemcomitans characterized by a 530-bp deletion in the promoter of the leukotoxin operon (Haubek 2010). Hypertonic NaCl extracts of bacteria from this clone analyzed by SDS-PAGE and Comassie staining reveald a protein pattern that was dominated by a 116 kDa band shown to be the leukotoxin (Johansson et al, 2000a) (Fig.…”

“…The within-species variable virulence may be attributed to a strain-to-strain variation in genome content and regulation of virulence gene expression (Kittichotirat et al, 2011). Future work with genomic characterization of A. actinomycetemcomitans might contribute to identify specific virulent clones other than the already well characterized highly leukotoxic JP2 clonal types (Haubek 2010;Kittichotirat et al, 2011). In addition, population genetic analyses of this bacterium have been giving information about global dissemination of this species and its strict horizontal transfer pattern together with the presence of several genetic peculiarities give also information about population trades Habek et al, 2007).…”