Leukotoxic Activity of Aggregatibacter actinomycetemcomitans and Periodontal Attachment Loss

Åberg, Carola Höglund; Haubek, Dorte; Kwamin, Francis; Johansson, Anders; Claesson, Rolf

doi:10.1371/journal.pone.0104095

Cited by 60 publications

(138 citation statements)

References 42 publications

(50 reference statements)

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“…A member of the repeats-in-toxin (RTX) family of pore-forming proteins, LtxA induces plasma membrane permeabilization and unregulated calcium influx into toxin-susceptible cells (13). LtxA expression varies among Aa strains and correlates with periodontal disease severity in colonized individuals (14). We hypothesized that similar to membranolytic pathways that mediate hypercitrullination in the RA joint (2), transient disruption of neutrophil membrane integrity by LtxA may drive the dysregulated activation of PAD enzymes through influx of extracellular calcium.…”

Section: Resultsmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans –induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

et al. 2016

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A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin-A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF). The effect of HLA-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients that were exposed to Aa. These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA.

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Section: Resultsmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans –induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

et al. 2016

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“…25 Leukotoxicity is substantially correlated with attachment loss in adolescents, indicating an important role of the toxin in the pathogenesis of AgP. 26 Among the non-oral infections, pneumonia caused by A. actinomycetemcomitans infections dominates of reports from adolescents. 27 There was an association to periodontitis in these A. actinomycetemcomitans infected individuals, but the virulence characteristic of these bacteria has not yet been examined.…”

Section: Aggregatibacter Actinomycetemcomitansmentioning

confidence: 99%

“…35 There is a strong association between the presence of highly leukotoxic A. actinomycetemcomitans, both of the JP2-genotype and some highly leukotoxic variants of the non-JP2 genotype, and the disease progression in the infected individuals studied. 17,23,26 These findings attract enhanced attention concerning the importance of leukotoxicity acting toward the defense mechanisms in the host response.…”

Section: Aggregatibacter Actinomycetemcomitansmentioning

confidence: 99%

Aggregatibacter actinomycetemcomitans: Virulence of its leukotoxin and association with aggressive periodontitis

2014

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“…A. actinomycetemcomitans exhibits two leukotoxic phenotypes: a minimally leukotoxic (non-JP2 genotype) and a highly leukotoxic (JP2 genotype) (5, 6). However, it has been shown that a subgroup of serotype b of the non-JP2 genotype also is highly leukotoxic (7). DNA sequence analysis of the Ltx promoter regions from these two clones revealed that the minimally leukotoxic genotype harbours a full-length promoter region, while the highly leukotoxic JP2 genotype is characterised by missing a 530 bp sequence of the Ltx promoter region (8).…”

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confidence: 99%

Effects ofAggregatibacter actinomycetemcomitansleukotoxin on neutrophil migration and extracellular trap formation

Hirschfeld

Roberts

Chapple

et al. 2016

Journal of Oral Microbiology

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BackgroundAggressive periodontitis is associated with the presence of Aggregatibacter actinomycetemcomitans, a leukotoxin (Ltx)-producing periodontal pathogen. Ltx has the ability to lyse white blood cells including neutrophils.ObjectivesThis study was aimed at investigating the interactions between neutrophils and Ltx with regard to the chemotactic properties of Ltx and the release of neutrophil extracellular traps (NETs).MethodsNeutrophils from healthy blood donors were isolated and incubated for 30 min and 3 h with increasing concentrations of Ltx (1, 10, and 100 ng/mL) as well as with A. actinomycetemcomitans strains (NCTC 9710 and HK 1651) producing different levels of Ltx. Formation of NETs and cell lysis were assessed by microscopy, fluorescence-based assays, and measurement of released lactate dehydrogenase. Neutrophil migration in response to different Ltx gradients was monitored by real-time video microscopy, and image analysis was performed using ImageJ software.ResultsAlthough Ltx (10 and 100 ng/mL) and the leukotoxic A. actinomycetemcomitans strain HK 1651 lysed some neutrophils, other cells were still capable of performing NETosis in a concentration-dependent manner. Low doses of Ltx and the weakly leukotoxic strain NCTC 9710 did not lead to neutrophil lysis, but did induce some NETosis. Furthermore, all three concentrations of Ltx enhanced random neutrophil movement; however, low directional accuracy was observed compared with the positive control (fMLP).ConclusionsThe results indicate that Ltx acts both as a neutrophil activator and also causes cell death. In addition, Ltx directly induces NETosis in neutrophils prior to cell lysis. In future studies, the underlying pathways involved in Ltx-meditated neutrophil activation and NETosis need to be investigated further.

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Leukotoxic Activity of Aggregatibacter actinomycetemcomitans and Periodontal Attachment Loss

Cited by 60 publications

References 42 publications

Aggregatibacter actinomycetemcomitans –induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

Aggregatibacter actinomycetemcomitans –induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

Aggregatibacter actinomycetemcomitans: Virulence of its leukotoxin and association with aggressive periodontitis

Effects ofAggregatibacter actinomycetemcomitansleukotoxin on neutrophil migration and extracellular trap formation

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