Proteomic and immunoproteomic analysis of Aggregatibacter actinomycetemcomitans JP2 clone strain HK1651

Rylev, Mette; Abduljabar, Ahmed B.; Reinholdt, Jesper; Ennibi, Oum Keltoum; Haubek, Dorte; Birkelund, Svend; Kilian, Mogens

doi:10.1016/j.jprot.2011.07.022

Cited by 16 publications

(18 citation statements)

References 48 publications

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“…S3C-D). This is consistent with the small population of healthy individuals that are infected with Aa , but have not developed periodontitis (21). Using the 100 th percentile of unexposed controls as a cut-off for positivity, anti-LtxA antibodies were strikingly associated with RA (43% vs 11% positivity; p<0.0001), indicating infection with leukotoxic strains of Aa in a large subset of patients.…”

Section: Resultssupporting

confidence: 88%

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: Resultssupporting

confidence: 88%

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

et al. 2016

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“…The outer membrane proteins (OMP) Omp18/16 (GI:293391272), Omp29 (GI:293390286; also referred to as OmpA and Omp34), Omp39 (GI:293391956), Omp100 (GI:293390333; also referred to as ApiA), and YaeT (GI:293390810) exhibit antigenicity in the host [50]–[53]. Notably, Omp39 and YaeT are antigenic in patients carrying the highly leukotoxic A. actinomycetemcomitans JP2 clone [52], and Omp29 is associated with the entry of A. actinomycetemcomitans into gingival epithelial cells [50]. Omp64 has been suggested to play a role in iron acquisition [51].…”

Section: Resultsmentioning

confidence: 99%

Proteomics of Protein Secretion by Aggregatibacter actinomycetemcomitans

2012

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The extracellular proteome (secretome) of periodontitis-associated bacteria may constitute a major link between periodontitis and systemic diseases. To obtain an overview of the virulence potential of Aggregatibacter actinomycetemcomitans , an oral and systemic human pathogen implicated in aggressive periodontitis, we used a combined LC-MS/MS and bioinformatics approach to characterize the secretome and protein secretion pathways of the rough-colony serotype a strain D7S. LC-MS/MS revealed 179 proteins secreted during biofilm growth. Further to confirming the release of established virulence factors (e.g. cytolethal distending toxin [CDT], and leukotoxin [LtxA]), we identified additional putative virulence determinants in the secretome. These included DegQ, fHbp, LppC, Macrophage infectivity protein (MIP), NlpB, Pcp, PotD, TolB, and TolC. This finding indicates that the number of extracellular virulence-related proteins is much larger than previously demonstrated, which was also supported by in silico analysis of the strain D7S genome. Moreover, our LC-MS/MS and in silico data revealed that at least Type I, II, and V secretion are actively used to excrete proteins directly into the extracellular space, or via two-step pathways involving the Sec/Tat systems for transport across the inner membrane, and outer membrane factors, secretins and auto-transporters, respectively for delivery across the outer membrane. Taken together, our results provide a molecular basis for further elucidating the role of A. actinomycetemcomitans in periodontal and systemic diseases.

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“…To yield the maximum proteome coverage, we carefully optimized the number of SCX fractions (20 fractions) as well as the elution concentrations so that peptides were evenly distributed over the 20 fractions for subsequent LC/MS shotgun sequencing. Ion exchange chromatography of urea extracted membrane preparations and analysis of individual fractions by LC/MS increased the identification of envelope proteins approximately fourfold in this study from previous studies of the A. actinomycetemcomitans proteome (Rylev et al ., ; Zijnge et al ., ).…”

Section: Discussionmentioning

confidence: 99%

The cell envelope proteome of Aggregatibacter actinomycetemcomitans

Smith

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Voogt

et al. 2014

Molecular Oral Microbiology

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Summary The cell envelope of Gram-negative bacteria serves a critical role in maintenance of cellular homeostasis, resistance to external stress, and host-pathogen interactions. Envelope protein composition is influenced by the physiological and environmental demands placed on the bacterium. In this study, we report a comprehensive compilation of cell envelope proteins from the periodontal and systemic pathogen Aggregatibacter actinomycetemcomitans VT1169, an afimbriated serotype b strain. The urea-extracted membrane proteins were identified by mass spectrometry-based shotgun proteomics. The membrane proteome, isolated from actively growing bacteria under normal laboratory conditions, included 648 proteins representing 28% of the predicted ORFs in the genome. Bioinformatic analyses were used to annotate and predict the cellular location and function of the proteins. Surface adhesins, porins, lipoproteins, numerous influx and efflux pumps, multiple sugar, amino acid and iron transporters, and components of the type I, II and V secretion systems were identified. Periplasmic space and cytoplasmic proteins with chaperone function were also identified. 107 proteins with unknown function were associated with the cell envelope. Orthologs of a subset of these uncharacterized proteins are present in other bacterial genomes, while others are found exclusively in A. actinomycetemcomitans. This knowledge will contribute to elucidating the role of cell envelope proteins in bacterial growth and survival in the oral cavity.

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Proteomic and immunoproteomic analysis of Aggregatibacter actinomycetemcomitans JP2 clone strain HK1651

Cited by 16 publications

References 48 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

Proteomics of Protein Secretion by Aggregatibacter actinomycetemcomitans

The cell envelope proteome of Aggregatibacter actinomycetemcomitans

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