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  • 1. Ahlstrand, Tuuli
    et al.
    Kovesjoki, Laura
    Maula, Terhi
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ihalin, Riikka
    Aggregatibacter actinomycetemcomitans LPS binds human interleukin-82019In: Journal of Oral Microbiology, ISSN 2000-2297, E-ISSN 2000-2297, Vol. 11, no 1Article in journal (Refereed)
    Abstract [en]

    Various gram-negative species sequester host cytokines using outer membrane proteins or surface modulation by sulfated polysaccharides. An outer membrane lipoprotein (BilRI) of the periodontal pathogen Aggregatibacter actinomycetemcomitans binds several cytokines, including interleukin (IL)-8. Because IL-8 is positively charged at physiological pH, we aimed to determine whether IL-8 interacts with negatively charged lipopolysaccharide (LPS). Binding was investigated using electrophoretic mobility shift assays and microwell-based time-resolved fluorometric immunoassay. LPS from each tested strain of A. actinomycetemcomitans (N = 13), Pseudomonas aeruginosa (N = 1) and Escherichia coli (N = 1) bound IL-8. The K-d value of the A. actinomycetemcomitans LPS-IL-8 interaction varied between 1.2-17 mu M irrespective of the serotype and the amount of phosphorus in LPS and was significantly lower than that of the BilRI-IL-8 interaction. Moreover, IL-8 interacted with whole A. actinomycetemcomitans cells and outer membrane vesicles. Hence, LPS might be involved in binding of IL-8 to the outer membrane of A. actinomycetemcomitans. This raises an interesting question regarding whether other gram-negative periodontal pathogens use LPS for IL-8 sequestering in vivo.

  • 2. Ahlstrand, Tuuli
    et al.
    Tuominen, Heidi
    Beklen, Arzu
    Torittu, Annamari
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sormunen, Raija
    Pöllänen, Marja T.
    Permi, Perttu
    Ihalin, Riikka
    A novel intrinsically disordered outer membrane lipoprotein of Aggregatibacter actinomycetemcomitans binds various cytokines and plays a role in biofilm response to interleukin-1β and interleukin-82017In: Virulence, ISSN 2150-5594, E-ISSN 2150-5608, Vol. 8, no 2, p. 115-134Article in journal (Refereed)
    Abstract [en]

    Intrinsically disordered proteins (IDPs) do not have a well-defined and stable 3-dimensional fold. Some IDPs can function as either transient or permanent binders of other proteins and may interact with an array of ligands by adopting different conformations. A novel outer membrane lipoprotein, bacterial interleukin receptor I (BilRI) of the opportunistic oral pathogen Aggregatibacter actinomycetemcomitans binds a key gatekeeper proinflammatory cytokine interleukin (IL)-1β. Because the amino acid sequence of the novel lipoprotein resembles that of fibrinogen binder A of Haemophilus ducreyi, BilRI could have the potential to bind other proteins, such as host matrix proteins. However, from the tested host matrix proteins, BilRI interacted with neither collagen nor fibrinogen. Instead, the recombinant non-lipidated BilRI, which was intrinsically disordered, bound various pro/anti-inflammatory cytokines, such as IL-8, tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IL-10. Moreover, BilRI played a role in the in vitro sensing of IL-1β and IL-8 because low concentrations of cytokines did not decrease the amount of extracellular DNA in the matrix of bilRI− mutant biofilm as they did in the matrix of wild-type biofilm when the biofilms were exposed to recombinant cytokines for 22 hours. BilRI played a role in the internalization of IL-1β in the gingival model system but did not affect either IL-8 or IL-6 uptake. However, bilRI deletion did not entirely prevent IL-1β internalization, and the binding of cytokines to BilRI was relatively weak. Thus, BilRI might sequester cytokines on the surface of A. actinomycetemcomitans to facilitate the internalization process in low local cytokine concentrations.

  • 3.
    Asikainen, Sirkka
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Doğan, Başak
    Department of Periodontology, Faculty of Dentistry, Marmara University, Istanbul, Turkey.
    Turgut, Zeynep
    Department of Periodontology, Gazi University, Ankara, Turkey.
    Paster, Bruce J
    Department of Molecular Genetics, The Forsyth Institute, Boston, Massachusetts, United States of America.
    Bodur, Aysen
    Department of Periodontology, Gazi University, Ankara, Turkey.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Specified species in gingival crevicular fluid predict bacterial diversity2010In: PloS one, ISSN 1932-6203, Vol. 5, no 10, p. e13589-Article in journal (Refereed)
    Abstract [en]

    Among a variety of detected species those traditionally classified as Gram-negative anaerobes growing in mature subgingival biofilms were the main predictors for species diversity in GCF samples as well as responsible for distinguishing GCF samples from PP samples. GCF bacteria may provide new prospects for studying dynamic properties of subgingival biofilms.

  • 4. Bao, Kai
    et al.
    Bostanci, Nagihan
    Thurnheer, Thomas
    Grossmann, Jonas
    Wolski, Witold E.
    Thay, Bernard
    Umeå University, Faculty of Medicine, Department of Odontology.
    Belibasakis, Georgios N.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Aggregatibacter actinomycetemcomitans H-NS promotes biofilm formation and alters protein dynamics of other species within a polymicrobial oral biofilm2018In: npj Biofilms and Microbiomes, ISSN 2055-5008, Vol. 4, no 12, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans is a Gram-negative organism, strongly associated with aggressive forms of periodontitis. An important virulence property of A. actinomycetemcomitans is its ability to form tenacious biofilms that can attach to abiotic as well as biotic surfaces. The histone-like (H-NS) family of nucleoid-structuring proteins act as transcriptional silencers in many Gram-negative bacteria. To evaluate the role of H-NS in A. actinomycetemcomitanshns mutant derivatives of serotype a strain D7S were generated. Characteristics of the hns mutant phenotype included shorter and fewer pili, and substantially lower monospecies biofilm formation relative to the wild type. Furthermore, the D7S hns mutant exhibited significantly reduced growth within a seven-species oral biofilm model. However, no apparent difference was observed regarding the numbers and proportions of the remaining six species regardless of being co-cultivated with D7S hnsor its parental strain. Proteomics analysis of the strains grown in monocultures confirmed the role of H-NS as a repressor of gene expression in A. actinomycetemcomitans. Interestingly, proteomics analysis of the multispecies biofilms indicated that the A. actinomycetemcomitanswild type and hns mutant imposed different regulatory effects on the pattern of protein expression in the other species, i.e., mainly Streptococcus spp., Fusobacterium nucleatum, and Veillonella dispar. Gene ontology analysis revealed that a large portion of the differentially regulated proteins was related to translational activity. Taken together, our data suggest that, apart from being a negative regulator of protein expression in A. actinomycetemcomitans, H-NS promotes biofilm formation and may be an important factor for survival of this species within a multispecies biofilm.

  • 5.
    Enow, Constance
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Mizunoe, Yoshimitsu
    Huang, Shengua
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Meier, Elke
    Benz, Roland
    Sauer-Eriksson, Elisabeth
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Localization and structure of the ClyA protein in Escherichia coli before secretion and pore-formationManuscript (preprint) (Other academic)
  • 6.
    Enow Oben Ayuk, Constance
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Zlatkov, Nikola
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Westermark, Marie
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Duperthuy, Marylise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Elevated recombinant clyA gene expression in the uropathogenic Escherichia coli strain 536, a clue to explain pathoadaptive mutations in a subset of extraintestinal E. coli strains2014In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 14, p. 216-Article in journal (Refereed)
    Abstract [en]

    There are at least four different variants of ΔclyA, suggesting that such deletions in clyA have arisen at more than one occasion. On the basis of this occurrence of the truncated clyA genes, we considered that there may be a patho-adaptive selection for deletions in clyA in extraintestinal pathogenic E. coli. In E. coli K-12 the clyA gene has been viewed as “cryptic” since it is tightly silenced by the nucleoid structuring protein H-NS. We constructed a restored clyA+ locus in derivatives of the UPEC strain 536 for further investigation of this hypothesis and, in particular, how the gene would be expressed. Our results show that the level of clyA+ expression is highly increased in the UPEC derivatives in comparison with the non-pathogenic E. coli K-12. Transcription of the clyA+ gene was induced to even higher levels when the SfaX regulatory protein was overproduced. The derivative with a restored clyA+ locus displayed a somewhat slower growth than the parental UPEC strain 536 when a sub-inhibitory concentration of the antimicrobial peptide Polymyxin B was added to the growth medium.

  • 7. Gustafsson, Erik
    et al.
    Karlsson, Stefan
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Odontology. Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
    Sögård, Peter
    Nilsson, Patric
    Arvidson, Staffan
    Mathematical modelling of the regulation of spa (protein A) transcription in Staphylococcus aureus.2009In: International journal of medical microbiology : IJMM, ISSN 1618-0607, Vol. 299, no 1, p. 65-74Article in journal (Refereed)
    Abstract [en]
    In the present work a general systems biology approach has been used to study the complex regulatory network controlling the transcription of the spa gene, encoding protein A, a major surface protein and an important virulence factor of Staphylococcus aureus. A valid mathematical model could be formulated using parameter values, which were fitted to quantitative Northern blot data from various S. aureus regulatory mutants using a gradient search method. The model could correctly predict spa expression levels in 4 different regulatory mutants not included in the parameter value search, and in 2 other S. aureus strains, SH1000 and UAMS-1. The mathematical model revealed that sarA and sarS seem to balance each other in a way that when the activating impact of sarS is small, e.g. in the wild-type, the repressive impact of sarA is small, while in an agr-deficient background, when the impact of sarS is maximal, the repressive impact of sarA is close to its maximum. Furthermore, the model revealed that Rot and SarS act synergistically to stimulate spa expression, something that was not obvious from experimental data. We believe that this mathematical model can be used to evaluate the significance of other putative interactions in the regulatory network governing spa transcription.
  • 8. Gustafsson, Erik
    et al.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Odontology. Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
    Maximal transcription of aur (aureolysin) and sspA (serine protease) in Staphylococcus aureus requires staphylococcal accessory regulator R (sarR) activity.2008In: FEMS Microbiology Letters, ISSN 0378-1097, E-ISSN 1574-6968, Vol. 284, no 2, p. 158-64Article in journal (Refereed)
    Abstract [en]

    Previous studies have shown that expression of aur (metalloprotease; aureolysin) and sspA (V8 protease; serine protease) in Staphylococcus aureus strain 8325-4 is maximal in the postexponential phase of growth, when the agr (RNAIII) system is activated. Transcription of aur and sspA is mainly regulated through repression by sarA and rot, and RNAIII stimulates protease production by inhibiting translation of rot mRNA. As SarR is a repressor of sarA, inactivation of sarR would result in downregulation of aur and sspA transcription. This was confirmed by mRNA analysis using quantitative real-time PCR. However, we found that sarR acted as a direct stimulator, i.e. its positive effect on aur and sspA transcription did not require sarA (or rot) per se. In addition, aur and sspA were dependent on sarR for maximal transcription. This stimulating role of sarR was not restricted to the rsbU-deficient laboratory strain 8325-4 but was also demonstrated in S. aureus strain SH1000 (rsbU-complemented derivative of 8325-4) and in one clinical isolate.

  • 9.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Höglund Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, D.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    The cagE gene sequence as a diagnostic marker to identify JP2 and non-JP2 highly leukotoxic Aggregatibacter actinomycetemcomitans serotype b strains.2017In: Journal of Periodontal Research, ISSN 0022-3484, E-ISSN 1600-0765, Vol. 52, no 5, p. 903-912Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND OBJECTIVE:Aggregatibacter actinomycetemcomitans is involved in oral and systemic infections, and is associated with, eg aggressive forms of periodontitis and with endocarditis. The cagE gene encodes a ≈39 kDa putative exotoxin expressed by A. actinomycetemcomitans. The level of conservation of cagE, and its possible significance in periodontal disease, has not yet been thoroughly investigated. In the present study, the role of the cagE gene as a diagnostic marker has been investigated.

    MATERIAL AND METHODS:We have used conventional polymerase chain reaction (PCR), quantitative PCR and whole genome sequencing data to determine the prevalence of cagE in A. actinomycetemcomitans based on analysis of: (i) 249 isolates, collected and cultivated in a Ghanaian longitudinal cohort study; (ii) a serotype b collection of 19 strains; and (iii) the 36 A. actinomycetemcomitans genomes available in the NCBI database.

    RESULTS:Whereas cagE was absent in the other serotypes, our data support that this gene sequence is linked to a virulent and highly leukotoxic group of serotype b strains, including both JP2 and non-JP2 genotypes of A. actinomycetemcomitans.

    CONCLUSION:We propose that cagE has the potential to be used as a PCR-based gene marker for the identification of a virulent and highly leukotoxic group of serotype b strains, including both JP2 and non-JP2 genotypes. This finding might be of importance in the risk assessment of the development of periodontal attachment loss in young individuals and hence suggested to be a relevant discovery in future development of new diagnostic tools and/or treatment strategies.

  • 10.
    Johansson, Anders
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Höglund-Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology.
    Haubek, Dorte
    Lindholm, Mark
    Umeå University, Faculty of Medicine, Department of Odontology.
    Jasim, Sarah
    Umeå University, Faculty of Medicine, Department of Odontology.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Genetic Profiling of Aggregatibacter actinomycetemcomitans Serotype B Isolated from Periodontitis Patients Living in Sweden2019In: Pathogens, ISSN 2076-0817, Vol. 8, no 3, p. 1-13, article id 153Article in journal (Refereed)
    Abstract [en]

    The bacterium Aggregatibacter actinomycetemcomitans is associated with aggressive forms of periodontitis and with systemic diseases, such as endocarditis. By assessing a Ghanaian longitudinal adolescent cohort, we earlier recognized the cagE gene as a possible diagnostic marker for a subgroup of JP2 and non-JP2 genotype serotype b A. actinomycetemcomitans strains, associated with high leukotoxicity as determined in a semi-quantitative cell assay. This group of A. actinomycetemcomitans is associated with the progression of attachment loss. In the present work, we used conventional polymerase chain reaction (PCR) and quantitative PCR to perform the cagE genotyping of our collection of 116 selected serotype b A. actinomycetemcomitans strains, collected over a period of 15 years from periodontitis patients living in Sweden. The A. actinomycetemcomitans strains carrying cagE (referred to as cagE+; n = 49) were compared to the cagE-negative strains (n = 67), present at larger proportions in the subgingival plaque samples, and were also much more prevalent in the young (≤35 years) compared to in the old (>35 years) group of patients. Our present results underline the potential use of cagE genotyping in the risk assessment of the development of periodontal attachment loss in Swedish adolescents.

  • 11. Kanasi, E
    et al.
    Dogan, B
    Karched, M
    Thay, B
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Asikainen, Sirkka
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Lack of Serotype Antigen in A. actinomycetemcomitans2010In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 89, no 3, p. 292-6Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans is divided into 6 serotypes. Occurrence of non-serotypeable strains is known, but background reasons are unclear. We hypothesized that non-serotypeable strains represent new serotypes or have altered expression of serotype-specific polysaccharide antigen (S-PA). We first characterized 311 strains from 189 individuals using both immunoassay- and PCR-based serotyping. Next, using natural human infection and rabbit immunization approaches, we clarified whether the phenotypically non-serotypeable strains expressed S-PA. Immunoassay identified serotypes a-f among 216 strains from 159 individuals. The remaining 95 strains from 30 individuals were phenotypically non-serotypeable. Yet, all these strains were identified by PCR-typing as serotype a-, b-, c-, or f. Non-serotypeability was confirmed by Western immunoblot with respective rabbit antisera. Patient sera remained non-reactive with autologous non-serotypeable strains at the serotype-specific region. Rabbit immunization with a phenotypically non-serotypeable strain induced no antibody production against S-PA. Thus, phenotypically non-serotypeable strains did not include novel serotypes, but lacked S-PA expression.

  • 12.
    Karched, Maribasappa
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ihalin, Rikka
    Eneslätt, Kjell
    Zhong, D
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR).
    Chen, C
    Asikainen, Sirkka
    Umeå University, Faculty of Medicine, Department of Odontology.
    Vesicle-independent extracellular release of a proinflammatory outer membrane lipoprotein in free-soluble form2008In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 28, no 8:18Article in journal (Refereed)
    Abstract [sv]

    Aggregatibacter actinomycetemcomitans is an oral bacterium associated with aggressively progressing periodontitis. Extracellular release of bacterial outer membrane proteins has been suggested to mainly occur via outer membrane vesicles. This study investigated the presence and conservation of peptidoglycan-associated lipoprotein (AaPAL) among A. actinomycetemcomitans strains, the immunostimulatory effect of AaPAL, and whether live cells release this structural outer membrane lipoprotein in free-soluble form independent of vesicles. RESULTS: The pal locus and its gene product were confirmed in clinical A. actinomycetemcomitans strains by PCR-restriction fragment length polymorphism and immunoblotting. Culturing under different growth conditions revealed no apparent requirement for the AaPAL expression. Inactivation of pal in a wild-type strain (D7S) and in its spontaneous laboratory variant (D7SS) resulted in pleiotropic cellular effects. In a cell culture insert model (filter pore size 0.02 um), AaPAL was detected from filtrates when strains D7S and D7SS were incubated in serum or broth in the inserts. Electron microscopy showed that A. actinomycetemcomitans vesicles (0.05-0.2 um) were larger than the filter pores and that there were no vesicles in the filtrates. The filtrates were immunoblot negative for a cytoplasmic marker, cyclic AMP (cAMP) receptor protein. An ex vivo model indicated cytokine production from human whole blood stimulated by AaPAL. CONCLUSIONS: Free-soluble AaPAL can be extracellularly released in a process independent of vesicles.

  • 13.
    Kieselbach, Thomas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Dataset of the proteome of purified outer membrane vesicles from the human pathogen Aggregatibacter actinomycetemcomintans2017In: Data in Brief, ISSN 2352-3409, Vol. 10, p. 426-431Article in journal (Refereed)
    Abstract [en]

    Abstract The Gram-negative bacterium Aggregatibacter actinomycetemcomitans is an oral and systemic pathogen, which is linked to aggressive forms of periodontitis and can be associated with endocarditis. The outer membrane vesicles (OMVs) of this species contain effector proteins such as cytolethal distending toxin (CDT) and leukotoxin (LtxA), which they can deliver into human host cells. The OMVs can also activate innate immunity through NOD1- and NOD2-active pathogen-associated molecular patterns. This dataset provides a proteome of highly purified OMVs from A. actinomycetemcomitans serotype e strain 173. The experimental data do not only include the raw data of the LC-MS/MS analysis of four independent preparations of purified OMVs but also the mass lists of the processed data and the Mascot.dat files from the database searches. In total 501 proteins are identified, of which 151 are detected in at least three of four independent preparations. In addition, this dataset contains the COG definitions and the predicted subcellular locations (PSORTb 3.0) for the entire genome of A. actinomycetemcomitans serotype e strain SC1083, which is used for the evaluation of the LC-MS/MS data. These data are deposited in ProteomeXchange in the public dataset PXD002509. In addition, a scientific interpretation of this dataset by Kieselbach et al. (2015) [2] is available at http://dx.doi.org/10.1371/journal.pone.0138591.

  • 14.
    Kieselbach, Thomas
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Zijnge, Vincent
    Granström, Elisabeth
    Umeå University, Faculty of Medicine, Department of Odontology.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Proteomics of Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0138591Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans is an oral and systemic pathogen associated with aggressive forms of periodontitis and with endocarditis. Outer membrane vesicles (OMVs) released by this species have been demonstrated to deliver effector proteins such as cytolethal distending toxin (CDT) and leukotoxin (LtxA) into human host cells and to act as triggers of innate immunity upon carriage of NOD1- and NOD2-active pathogen-associated molecular patterns (PAMPs). To improve our understanding of the pathogenicity-associated functions that A. actinomycetemcomitans exports via OMVs, we studied the proteome of density gradient-purified OMVs from a rough-colony type clinical isolate, strain 173 (serotype e) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This analysis yielded the identification of 151 proteins, which were found in at least three out of four independent experiments. Data are available via ProteomeXchange with identifier PXD002509. Through this study, we not only confirmed the vesicle-associated release of LtxA, and the presence of proteins, which are known to act as immunoreactive antigens in the human host, but we also identified numerous additional putative virulence-related proteins in the A. actinomycetemcomitans OMV proteome. The known and putative functions of these proteins include immune evasion, drug targeting, and iron/nutrient acquisition. In summary, our findings are consistent with an OMV-associated proteome that exhibits several offensive and defensive functions, and they provide a comprehensive basis to further disclose roles of A. actinomycetemcomitans OMVs in periodontal and systemic disease.

  • 15.
    Lindholm, Mark
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Aung, Kyaw Min
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Role of OmpA1 and OmpA2 in Aggregatibacter actinomycetemcomitans and Aggregatibacter aphrophilus serum resistance2019In: Journal of Oral Microbiology, ISSN 2000-2297, E-ISSN 2000-2297, Vol. 11, no 1, article id 1536192Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans and Aggregatibacter aphrophilus belong to the HACEK group of fastidious Gram-negative organisms, a recognized cause of infective endocarditis. A. actinomycetemcomitans is also implicated in aggressive forms of periodontitis. We demonstrated that A. aphrophilus strains, as A. actinomycetemcomitans are ubiquitously serum resistant. Both species encode two Outer membrane protein A paralogues, here denoted OmpA1 and OmpA2. As their respective pangenomes contain several OmpA1 and OmpA2 alleles, they represent potential genotypic markers. A naturally competent strain of A. actinomycetemcomitans and A. aphrophilus, respectively were used to elucidate if OmpA1 and OmpA2 contribute to serum resistance. Whereas OmpA1 was critical for survival of A. actinomycetemcomitans D7SS in 50% normal human serum (NHS), serum resistant ompA1 mutants were fortuitously obtained, expressing enhanced levels of OmpA2. Similarly, OmpA1 rather than OmpA2 was a major contributor to serum resistance of A. aphrophilus HK83. Far-Western blot revealed that OmpA1AA, OmpA2AA, and OmpA1AP can bind to C4-binding protein, an inhibitor of classical and mannose-binding lectin (MBL) complement activation. Indeed, ompA1 mutants were susceptible to these pathways, but also to alternative complement activation. This may at least partly reflect a compromised outer membrane integrity but is also consistent with alternative mechanisms involved in OmpA-mediated serum resistance.

  • 16.
    Oscarsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lindholm, Mark
    Umeå University, Faculty of Medicine, Department of Odontology.
    Höglund-Åberg, Carola
    Umeå University, Faculty of Medicine, Department of Odontology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Tools of Aggregatibacter actinomycetemcomitans to Evade the Host Response2019In: Journal of Clinical Medicine, ISSN 2077-0383, Vol. 8, no 7, article id 1079Article in journal (Refereed)
    Abstract [en]

    Periodontitis is an infection-induced inflammatory disease that affects the tooth supporting tissues, i.e., bone and connective tissues. The initiation and progression of this disease depend on dysbiotic ecological changes in the oral microbiome, thereby affecting the severity of disease through multiple immune-inflammatory responses. Aggregatibacter actinomycetemcomitans is a facultative anaerobic Gram-negative bacterium associated with such cellular and molecular mechanisms associated with the pathogenesis of periodontitis. In the present review, we outline virulence mechanisms that help the bacterium to escape the host response. These properties include invasiveness, secretion of exotoxins, serum resistance, and release of outer membrane vesicles. Virulence properties of A. actinomycetemcomitans that can contribute to treatment resistance in the infected individuals and upon translocation to the circulation, also induce pathogenic mechanisms associated with several systemic diseases.

  • 17.
    Oscarsson, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Karched, Maribasappa
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Thay, Bernard
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Chen, Casey
    Asikainen, Sirkka
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Proinflammatory effect in whole blood by free soluble bacterial components released from planktonic and biofilm cells2008In: BMC Microbiology, ISSN 1471-2180, E-ISSN 1471-2180, Vol. 8, no 206, p. 13-Article in journal (Refereed)
    Abstract [en]

    BackgroundAggregatibacter actinomycetemcomitans is an oral bacterium associated with aggressive forms of periodontitis. Increasing evidence points to a link between periodontitis and cardiovascular diseases, however, the underlying mechanisms are poorly understood. This study investigated the pathogenic potential of free-soluble surface material, released from live planktonic and biofilm A. actinomycetemcomitans cells.

    Results: By employing an ex vivo insert model (filter pore size 20 nm) we demonstrated that the A. actinomycetemcomitans strain D7S and its derivatives, in both planktonic and in biofilm life-form, released free-soluble surface material independent of outer membrane vesicles. This material clearly enhanced the production of several proinflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MIP-1β) in human whole blood, as evidenced by using a cytokine antibody array and dissociation-enhanced-lanthanide-fluorescent-immunoassay. In agreement with this, quantitative real-time PCR indicated a concomitant increase in transcription of each of these cytokine genes. Experiments in which the LPS activity was blocked with polymyxin B showed that the stimulatory effect was only partly LPS-dependent, suggesting the involvement of additional free-soluble factors. Consistent with this, MALDI-TOF-MS and immunoblotting revealed release of GroEL-like protein in free-soluble form. Conversely, the immunomodulatory toxins, cytolethal distending toxin and leukotoxin, and peptidoglycan-associated lipoprotein, appeared to be less important, as evidenced by studying strain D7S cdt/ltx double, and pal single mutants. In addition to A. actinomycetemcomitans a non-oral species, Escherichia coli strain IHE3034, tested in the same ex vivo model also released free-soluble surface material with proinflammatory activity.

    ConclusionA. actinomycetemcomitans, grown in biofilm and planktonic form, releases free-soluble surface material independent of outer membrane vesicles, which induces proinflammatory responses in human whole blood. Our findings therefore suggest that release of surface components from live bacterial cells could constitute a mechanism for systemic stimulation and be of particular importance in chronic localized infections, such as periodontitis.

  • 18.
    Rompikuntal, Pramod K.
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Vdovikova, Svitlana
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Duperthuy, Marylise
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Johnson, Tanya L.
    Åhlund, Monika
    Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Lundmark, Richard
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sandkvist, Maria
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Outer Membrane Vesicle-Mediated Export of Processed PrtV Protease from Vibrio cholerae2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 7, article id e0134098Article in journal (Refereed)
    Abstract [en]

    Background Outer membrane vesicles (OMVs) are known to release from almost all Gram-negative bacteria during normal growth. OMVs carry different biologically active toxins and enzymes into the surrounding environment. We suggest that OMVs may therefore be able to transport bacterial proteases into the target host cells. We present here an analysis of the Vibrio cholerae OMV-associated protease PrtV. Methodology/Principal Findings In this study, we demonstrated that PrtV was secreted from the wild type V. cholerae strain C6706 via the type II secretion system in association with OMVs. By immunoblotting and electron microscopic analysis using immunogold labeling, the association of PrtV with OMVs was examined. We demonstrated that OMV-associated PrtV was biologically active by showing altered morphology and detachment of cells when the human ileocecum carcinoma (HCT8) cells were treated with OMVs from the wild type V. cholerae strain C6706 whereas cells treated with OMVs from the prtV isogenic mutant showed no morphological changes. Furthermore, OMV-associated PrtV protease showed a contribution to bacterial resistance towards the antimicrobial peptide LL-37. Conclusion/Significance Our findings suggest that OMVs released from V. cholerae can deliver a processed, biologically active form of PrtV that contributes to bacterial interactions with target host cells.

  • 19.
    Rompikuntal, Pramod Kumar
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Thay, Bernard
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Khan, Muhammad Khanzeb
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
    Alanko, Jonna
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Penttinen, Anna-Maija
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Asikainen, Sirkka
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Perinuclear localization of internalized outer membrane vesicles carrying active cytolethal distending toxin (CDT) from aggregatibacter actinomycetemcomitans2012In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 80, no 1, p. 31-42Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans is implicated in aggressive forms of periodontitis. Similar to several other Gram-negative species this organism produces and excretes a cytolethal distending toxin (CDT), a genotoxin associated with cell distention, G(2) cell cycle arrest and/or apoptosis in many mammalian cell types. In this study we have identified A. actinomycetemcomitans outer membrane vesicles (OMVs) as a vehicle for simultaneous delivery of multiple proteins, including CDT into human cells. The OMV proteins were internalized in both HeLa cells and human gingival fibroblasts (HGF) via a mechanism of OMV fusion with lipid rafts in the plasma membrane. The active toxin unit, CdtB was localized inside the nucleus of the intoxicated cells, whereas OmpA and proteins detected using an antibody specific to whole A. actinomycetemcomitans serotype a cells had a perinuclear distribution. In accordance with a tight association of CdtB with OMVs, vesicles isolated from A. actinomycetemcomitans strain D7SS (serotype a) in contrast to OMVs from a D7SS cdtABC mutant induced a cytolethal distending effect on HeLa and HGF cells, indicating that OMV-associated CDT was biologically active. Association of CDT with OMVs was also observed in A. actinomycetemcomitans isolates, belonging to serotypes b, and c, respectively, indicating that OMV-mediated release of CDT may be conserved in A. actinomycetemcomitans. Although, the role of A. actinomycetemcomitans OMVs in periodontal disease has not yet been elucidated, our present data suggest that OMVs could deliver biologically active CDT and additional virulence factors into susceptible cells of the periodontium.

  • 20.
    Thay, Bernard
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Damm, Anna
    University of Cologne.
    Kufer, Thomas
    University of Cologne.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Aggregatibacter actinomycetemcomitans Outer Membrane Vesicles are internalized in human host cells and trigger NOD1- and NOD2-dependent NF-κB activation2014In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 82, no 10, p. 4034-4046Article in journal (Refereed)
    Abstract [en]

    Aggregatibacter actinomycetemcomitans is an oral and systemic pathogen associated with aggressive forms of periodontitis, and endocarditis. We recently demonstrated that OMVs disseminated by A. actinomycetemcomitans could deliver multiple proteins including biologically active cytolethal distending toxin (CDT) into the cytosol of HeLa cells and human gingival fibroblasts (HGF). In the present work we have used immunoelectron- and confocal microscopy analysis, and fluorescently labeled vesicles to further investigate mechanisms for A. actinomycetemcomitans OMV-mediated delivery of bacterial antigens to these host cells. Our results supported that OMVs were internalized into the perinuclear region of HeLa cells and HGF. Co-localization analysis revealed that internalized OMVs co-localized with the endoplasmic reticulum, and carried antigens, detected using an antibody specific to whole A. actinomycetemcomitans serotype a cells. Consistent with OMV internalization mediating intracellular antigen exposure, the vesicles acted as strong inducers of cytoplasmic peptidoglycan sensor NOD1- and NOD2-dependent NF-κB activation in human embryonic kidney cells. Moreover, NOD1 was the main sensor of OMV-delivered peptidoglycan in myeloid THP1 cells, contributing to the overall inflammatory responses induced by the vesicles. This work reveals a role of A. actinomycetemcomitans OMVs as a trigger of innate immunity via carriage of NOD1- and NOD2-active PAMPs.

  • 21.
    Thay, Bernard
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Wai, Sun Nyunt
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology.
    Staphylococcus aureus alpha-toxin-dependent induction of host cell death by membrane-derived vesicles2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, article id e54661Article in journal (Refereed)
    Abstract [en]

    Staphylococcus aureus causes a wide spectrum of infections in humans, ranging from superficial cutaneous infections, infections in the circum-oral region, to life-threatening bacteremia. It was recently demonstrated that Gram-positive organisms such as S. aureus liberate membrane-derived vesicles (MVs), which analogously to outer membrane vesicles (OMVs) of Gram-negative bacteria can play a role in delivering virulence factors to host cells. In the present study we have shown that cholesterol-dependent fusion of S. aureus MVs with the plasma membrane represents a route for delivery of a key virulence factor, α-toxin (α-hemolysin; Hla) to human cells. Most S. aureus strains produce this 33-kDa pore-forming protein, which can lyse a wide range of human cells, and induce apoptosis in T-lymphocytes. Our results revealed a tight association of biologically active α-toxin with membrane-derived vesicles isolated from S. aureus strain 8325-4. Concomitantly, α-toxin contributed to HeLa cell cytotoxicity of MVs, and was the main vesicle-associated protein responsible for erythrocyte lysis. In contrast, MVs obtained from an isogenic hla mutant were significantly attenuated with regards to both causing lysis of erythrocytes and death of HeLa cells. This is to our knowledge the first recognition of an S. aureus MV-associated factor contributing to host cell cytotoxicity.

  • 22.
    Wai, Sun Nyunt
    et al.
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Lindmark, Barbro
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Söderblom, Tomas
    Takade, Akemi
    Westermark, Marie
    Oscarsson, Jan
    Jass, Jana
    Richter-Dahlfors, Agneta
    Mizunoe, Yoshimitsu
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Biology (Faculty of Medicine).
    Vesicle-mediated export and assembly of pore-forming oligomers of the enterobacterial ClyA cytotoxin.2003In: Cell, ISSN 0092-8674, Vol. 115, no 1, p. 25-35Article in journal (Refereed)
    Abstract [en]

    The ClyA protein is a pore-forming cytotoxin expressed by Escherichia coli and some other enterobacteria. It confers cytotoxic activity toward mammalian cells, but it has remained unknown how ClyA is surface exposed and exported from bacterial cells. Outer-membrane vesicles (OMVs) released from the bacteria were shown to contain ClyA protein. ClyA formed oligomeric pore assemblies in the OMVs, and the cytotoxic activity toward mammalian cells was considerably higher than that of ClyA protein purified from the bacterial periplasm. The redox status of ClyA correlated with its ability to form the oligomeric pore assemblies. In bacterial cells with a defective periplasmic disulphide oxidoreductase system, the ClyA protein was phenotypically expressed in a constitutive manner. The results define a vesicle-mediated transport mechanism in bacteria, and our findings show that the localization of proteins to OMVs directly may contribute to the activation and delivery of pathogenic effector proteins.

  • 23. Zijnge, Vincent
    et al.
    Kieselbach, Thomas
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Oscarsson, Jan
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Proteomics of protein secretion by aggregatibacter actinomycetemcomitans2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 7, p. e41662-Article in journal (Refereed)
    Abstract [en]

    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.

1 - 23 of 23
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