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Objectives: Earlier reports suggested that aggressive periodontitis is common in certain African populations and is associated with the JP2 clone of Aggregatibacter actinomycetemcomitans (Aa). There are few studies that investigated the type of microorganisms that colonize the subgingival sites in young subjects inflicted with a subcategory of aggressive periodontitis that is associated with the Aa-JP2 clone. Hence, the objective of this study was to characterize the subgingival microbiome of JP2 clone-associated aggressive periodontitis. Methods: The study subjects were drawn from a large survey among 14-18 years old schoolchildren in Morocco. The sample included 7 JP2-positive aggressive periodontitis subjects and 14 JP2-negative controls. The controls were selected to be either JP2-positive, JP2-negative (but Aa positive), or Aa-negative. Subgingival samples from these subjects were sequenced for the V1-V3 region (16S rRNA gene) on a Miseq platform. High-quality, non-chimeric merged reads were classified with our previously reported BLASTn-algorithm. Downstream analysis was performed with QIIME and LEfSe. Results: There were no significant differences between the groups in species richness. However, aggressive periodontitis subjects showed significantly lower alpha diversity. The microbiomes of aggressive periodontitis clustered distinctively from the controls. However, there was no significant separation between the subgroups of the control group. Species associated with health included Streptococcus spp., Haemophilus spp., Neisseria spp., Gemella spp., Rothia spp., Fusobacterium nucleatum subsp. polymorphum, Porphyromonas oral taxon 279, Veillonella parvula, Granulicatella adiacens and Lautropia mirabilis. Important periodontal pathogens, including Treponema spp., Fretibacterium spp. P. gingivalis and Tannerella forsythia were significantly enriched in aggressive periodontitis subjects. However, the taxa detected in high abundance and showed strongest association with aggressive periodontitis but not the controls were Pseudomonas oral taxon C61 and Enterobacter cloacae. Conclusions: The results suggest that several periodontal pathogens involved in chronic periodontitis also play a role in aggressive periodontitis. Future studies should investigate the role of Pseudomonas and Enterobacter spp. in the pathogenesis of aggressive periodontitis. / Oral Biology

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.

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