| 1. |
- Egesten, Arne, et al.
(författare)
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Binding of albumin promotes bacterial survival at the epithelial surface.
- 2011
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; Dec, s. 2469-2476
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Tidskriftsartikel (refereegranskat)abstract
- Albumin (HSA) is the dominating protein in human plasma. Many bacterial species, especially streptococci, express surface proteins that bind HSA with high specificity and affinity, but the biological consequences of these protein-protein interactions are poorly understood. Group G streptococci (GGS), carrying the HSA-binding protein G, colonize the skin and the mucosa of the upper respiratory tract, mostly without causing disease. In case of bacterial invasion, pro-inflammatory cytokines are released that activate the epithelium to produce antibacterial peptides, in particular the chemokine MIG/CXCL9. In addition, the inflammation causes capillary leakage and extravasation of HSA and other plasma proteins; environmental changes at the epithelial surface to which the bacteria need to respond. In this study, we find that GGS adsorb HSA from both saliva and plasma via binding to protein G, and that HSA bound to protein G binds and inactivates the antibacterial MIG/CXCL9 peptide. Another surface protein of GGS, FOG, was found to mediate adherence of the bacteria to pharyngeal epithelial cells through interaction with glycosaminoglycans. This adherence was not affected by the activation of the epithelium with a combination of IFN-γ and TNF-α, leading to the production of MIG/CXCL9. However, at the activated epithelial surface, adherent GGS were protected against killing by MIG/CXCL9 through protein G dependent HSA-coating. The findings identify a previously unknown bacterial survival strategy that help to explain the evolution of HSA-binding proteins among bacterial species of the normal human microbiota.
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| 2. |
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| 3. |
- Frick, Inga-Maria, et al.
(författare)
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Identification of a novel protein promoting the colonization and survival of Finegoldia magna, a bacterial commensal and opportunistic pathogen.
- 2008
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Ingår i: Molecular Microbiology. - : Wiley. - 1365-2958 .- 0950-382X. ; 70, s. 695-708
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Tidskriftsartikel (refereegranskat)abstract
- Anaerobic bacteria dominate the human normal microbiota but strikingly little is known about these commensals. Finegoldia magna is a Gram-positive anaerobe found in the skin and at other non-sterile body surfaces, but it is also an opportunistic pathogen. This study describes a novel protein designated FAF (F. magnaAdhesion Factor) and expressed by more than ninety percent of F. magna isolates. The protein is present in substantial quantities at the F.magna surface but is also released from the surface. FAF forms large protein aggregates in solution and surface-associated FAF causes bacterial clumping. In skin F. magna bacteria were localized to the epidermis, where they adhere to basement membranes. FAF was found to mediate this adhesion via interactions with BM-40, a basement membrane protein. The biological significance of FAF is further underlined by the observation that it blocks the activity of LL-37, a major human antibacterial peptide. Altogether, the data demonstrate that FAF plays an important role in colonization and survival of F. magna in the human host.
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| 4. |
- Kahn, Fredrik, et al.
(författare)
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Antibodies against a surface protein of Streptococcus pyogenes promote a pathological inflammatory response.
- 2008
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Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 4:9
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcal toxic shock syndrome (STSS) caused by Streptococcus pyogenes is a clinical condition with a high mortality rate despite modern intensive care. A key feature of STSS is excessive plasma leakage leading to hypovolemic hypotension, disturbed microcirculation and multiorgan failure. Previous work has identified a virulence mechanism in STSS where M1 protein of S. pyogenes forms complexes with fibrinogen that activate neutrophils to release heparin-binding protein (HBP), an inducer of vascular leakage. Here, we report a marked inter-individual difference in the response to M1 protein-induced HBP release, a difference found to be related to IgG antibodies directed against the central region of the M1 protein. To elicit massive HBP release, such antibodies need to be part of the M1 protein-fibrinogen complexes. The data add a novel aspect to bacterial pathogenesis where antibodies contribute to the severity of disease by promoting a pathologic inflammatory response.
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| 5. |
- Murphy, Elizabeth, et al.
(författare)
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Identification of molecular mechanisms used by Finegoldia magna to penetrate and colonise human skin.
- 2014
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Ingår i: Molecular Microbiology. - : Wiley. - 1365-2958 .- 0950-382X. ; 94:2, s. 403-417
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Tidskriftsartikel (refereegranskat)abstract
- Finegoldia magna is a Gram-positive anaerobic commensal of the human skin microbiota, but also known to act as an opportunistic pathogen. Two primary virulence factors of F. magna are the subtilisin-like extracellular serine protease SufA and the adhesive protein FAF. This study examines the molecular mechanisms F. magna uses when colonising or establishing an infection in the skin. FAF was found to be essential in the initial adherence of F. magna to human skin biopsies. In the upper layers of the epidermis FAF mediates adhesion through binding to galectin-7 - a keratinocyte cell marker. Once the bacteria moved deeper into the skin to the basement membrane layer, SufA was found to degrade collagen IV which forms the backbone structure of the basement membrane. It also degraded collagen V, whereby F. magna could reach deeper dermal tissue sites. In the dermis, FAF interacts with collagen V and fibrillin, which presumably helps the bacteria to establish infection in this area. The findings of this study paint a clear picture of how F. magna interacts with human skin and explain how it is such a successful opportunistic pathogen in chronic wounds and ulcers.
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| 6. |
- Nylander, Anja, et al.
(författare)
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An investigation of the interaction between red blood cells and Streptococcus pyogenes
- 2010
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Konferensbidrag (refereegranskat)abstract
- Blood group antigens may be used as receptors by pathogens when infecting their hosts. Different blood groups therefore can be disease susceptibility factors. Thus, pathogens may have exerted a selection pressure on the evolution of blood group diversity. One aim of our study was to identify red blood cell (RBC) membrane structures that are bound by the common human pathogen. Streptococcus pyogenes, responsible for conditions like pharyngitis, Scarlet fever, necrotizing fasciitis and rheumatic heart disease. We also wanted to explore any differences in the ability of S. pyogenes to agglutinate RBC of different ABO groups and of selected null blood group phenotypes.Solubilized RBC membranes were incubated with different strains of S. pyogenes. RBC proteins that bound to bacteria were eluted and separated by SDS-PAGE. In our initial studies, a strong band at ~58 kDa and a weaker band at ~28 kDa were visualized by Coomassie staining. Subsequent analysis by mass spectrometry and Western blotting revealed the bands to correspond to IgG heavy and light chains. The IgG-related bands were strongest for bacterial strains expressing both protein H and M protein, surface structures known to bind IgG, while weaker or no bands were detected in those strains lacking one or both proteins. Results from subsequent experiments indicated that the interaction between S. pyogenes and RBCs was not limited to IgG, but that a number of other RBC membrane structures appear to bind specifically to S. pyogenes. Those proteins are currently being analysed by mass spectrometry.In agglutination studies of S. pyogenes and RBCs, either sensitised with IgG or stripped of IgG we confirmed that IgG has a role in the binding of RBCs by S. pyogenes. We observed no difference in the ability of S. pyogenes to agglutinate RBCs of different ABO groups, indicating that the ABO-specific differences in RBC surface oligosaccharides are not recognized. When we tested a panel of RBCs with rare null phenotypes we found that cells of the Helgeson phenotype, expressing very low levels of the Knops antigens on complement receptor 1 (CR1), agglutinated more weakly than other common and rare RBCs tested.We are still puzzled by the fact that the hemagglutination is stronger for S. pyogenes strains lacking the M-protein, known to bind both complement and IgG on the surface of the bacteria. Our hypothesis is that there might be some repulsive force acting between the M-protein and surface of RBC, making the interaction stronger when the M-protein is missing. This is supported by agglutination studies with papain-treated RBCs, where the negative charge is reduced.IgG is known to bind senescent cell antigens on erythroid band 3 and thus the amount of IgG increases on the RBC surface as it ages. We speculated that binding to IgG on the RBC surface by S. pyogenes could be a way to selectively target aged RBCs, possibly to acquire heme as a source of iron. Attempts to separate RBCs according to age were made on density gradients, followed by agglutination studies of the different fractions. Our initial results did not demonstrate any conclusive differences. Our data indicate that interactions between S. pyogenes and RBC are mediated at least through IgG and CR1 on the RBC surface. The clinical importance awaits exploration but may be relevant in the identification of resistance factors to infections among humans, and could thus lead to the development of alternative ways to treat infections caused by S. pyogenes.
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| 7. |
- Oehmcke, Sonja, et al.
(författare)
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Treatment of invasive streptococcal infection with a peptide derived from human high molecular weight kininogen.
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 114:2, s. 444-451
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Tidskriftsartikel (refereegranskat)abstract
- Sepsis and septic shock remain an important medical problem, emphasizing the need to identify novel therapeutic opportunities. Hypovolemic hypotension, coagulation dysfunction, disturbed microcirculation, and multiorgan failure due to vascular leakage are often observed in these severe conditions. In the present study, we find that HKH20, a peptide derived from human high molecular weight kininogen (HK), down-regulates inflammatory reactions caused by Streptococcus pyogenes in a mouse model of sepsis. HK is a component of the pro-inflammatory and pro-coagulant contact system. Activation of the contact system in the bloodstream by S. pyogenes leads to massive tissue damage in the lungs of the infected mice, which eventually results in the death of the animals. HKH20 inhibits activation of the contact system and protects mice with invasive S. pyogenes infection from lung damage. In combination with clindamycin treatment, the peptide also significantly prolongs the survival of infected mice.
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| 8. |
- Wollein Waldetoft, Kristofer, et al.
(författare)
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Streptococcal surface proteins activate the contact system and control its antibacterial activity.
- 2012
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 287:30, s. 25010-25018
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Tidskriftsartikel (refereegranskat)abstract
- Group G streptococci (GGS) are important bacterial pathogens in humans. Here we investigate the interactions between GGS and the contact system, a pro-coagulant and pro-inflammatory proteolytic cascade, which upon activation also generates antibacterial peptides. Two surface proteins of GGS, protein FOG and protein G (PG), were found to bind contact system proteins. Experiments utilizing contact protein deficient human plasma and isogenic GGS mutant strains lacking FOG or PG, showed that FOG and PG both activate the pro-coagulant branch of the contact system. In contrast, only FOG induced cleavage of high molecular weight kininogen (HK), generating the pro-inflammatory bradykinin peptide and additional HK fragments containing the antimicrobial peptide NAT-26. PG, on the other hand, protected the bacteria against the antibacterial effect of NAT-26. These findings underline the significance of the contact system in innate immunity, and demonstrate that GGS have evolved surface proteins to exploit and modulate its effects.
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