| 61. |
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| 62. |
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| 63. |
- Herwald, Heiko, et al.
(författare)
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Streptococcal cysteine proteinase releases kinins: a novel virulence mechanism
- 1996
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Ingår i: Journal of Experimental Medicine. - 1540-9538. ; 184:2, s. 665-673
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Tidskriftsartikel (refereegranskat)abstract
- Previous work has indicated a crucial role for the extracellular cysteine proteinase of Streptococcus pyogenes in the pathogenicity and virulence of this important human pathogen. Here we find that the purified streptococcal cysteine proteinase releases biologically active kinins from their purified precursor protein, H-kininogen, in vitro, and from kininogens present in the human plasma, ex vivo. Kinin liberation in the plasma is due to the direct action of the streptococcal proteinase on the kininogens, and does not involve the previous activation of plasma prekallikrein, the physiological plasma kininogenase. Judged from the amount of released plasma kinins the bacterial proteinase is highly efficient in its action. This is also the case in vivo. Injection of the purified cysteine proteinase into the peritoneal cavity of mice resulted in a progressive cleavage of plasma kininogens and the concomitant release of kinins over a period of 5 h. No kininogen degradation was seen in mice when the cysteine proteinase was inactivated by the specific inhibitor, Z-Leu-Val-Gly-CHN2, before administration. Intraperitoneal administration into mice of living S. pyogenes bacteria producing the cysteine proteinase induced a rapid breakdown of endogenous plasma kininogens and release of kinins. Kinins are hypotensive, they increase vascular permeability, contract smooth muscle, and induce fever and pain. The release of kinins by the cysteine proteinase of S. pyogenes could therefore represent an important and previously unknown virulence mechanism in S. pyogenes infections.
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| 64. |
- Holm, Karin, et al.
(författare)
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Activation of the contact system at the surface of Fusobacterium necrophorum: a possible virulence mechanism in Lemierre's syndrome.
- 2011
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Ingår i: Infection and Immunity. - 1098-5522. ; 79:8, s. 3284-3290
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Tidskriftsartikel (refereegranskat)abstract
- Fusobacterium necrophorum causes Lemièrre's syndrome, a serious disease with septic thrombophlebitis of the internal jugular vein, pulmonary involvement and systemic inflammation. The contact system is a link between inflammation and coagulation and contact activation by the bacteria could therefore contribute to the abnormal coagulation and inflammation seen in patients with Lemièrre's syndrome. In this study, F. necrophorum was found to bind radiolabeled high molecular weight kininogen (HK), a central component of the contact system. Binding was inhibited by the addition of unlabeled HK and domain D5 of HK, but not by other components of the contact system, indicating a specific interaction mediated through the D5 region. Binding of HK was significantly reduced after pre-treatment of the bacteria with trypsin, suggesting that surface proteins are involved in HK binding. Incubation of the bacteria with human plasma resulted in a breakdown pattern of HK suggestive of bradykinin release, and bradykinin was also detected in the supernatant. In addition, we show that factor XI (FXI), another component of the contact system, binds to F. necrophorum, and that the bound FXI reconstitutes the activated partial thromboplastin time (aPTT) of FXI-deficient plasma. Thrombin activity was detected at the surface of the bacteria following incubation with plasma, indicating that the intrinsic pathway of coagulation is activated at the surface. This activity was completely blocked by inhibitors of the contact system. The combined results show that the contact system is activated at the surface of F. necrophorum, suggesting a pathogenic role for this system in Lemièrre's syndrome.
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| 65. |
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| 66. |
- Jarva, Hanna, et al.
(författare)
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Streptococcus pneumoniae evades complement attack and opsonophagocytosis by expressing the pspC locus-encoded Hic protein that binds to short consensus repeats 8-11 of factor H
- 2002
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Ingår i: Journal of Immunology. - 1550-6606. ; 168:4, s. 1886-1894
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Tidskriftsartikel (refereegranskat)abstract
- Streptococcus pneumoniae is an important cause of upper and lower respiratory tract infections, meningitis, peritonitis, bacterial arthritis, and sepsis. Here we have studied a novel immune evasion mechanism of serotype 3 pneumococci, which are particularly resistant to phagocytosis. On their surfaces the bacteria express the factor H-binding inhibitor of complement (Hie), a protein of the pneumococcal surface protein C family. Using radioligand binding, microtiter plate assays, surface plasmon resonance analysis, and recombinant constructs of factor H, we located the binding site of Hie to short consensus repeats (SCRs) 8-11 in the middle part of factor H. This represents a novel microbial interaction region on factor H. The only other ligand known so far for SCRs 8-11 of factor H is C-reactive protein (CRP), an acute phase protein that binds to the pneumococcal C-polysaccharide. The binding sites of Hie and CRP within the SCR8-11 region were different, however, because CRP did not inhibit the binding of Hie and required calcium for binding. Binding of factor H to Hic-expressing pneumococci promoted factor I-mediated cleavage of C3b and restricted phagocytosis of pneumococci. Thus, virulent pneumococci avoid complement attack and opsonophagocytosis by recruiting functionally active factor H with the Hie surface protein. Hie binds to a previously unrecognized microbial interaction site in the middle part of factor H.
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| 67. |
- Johansson, Björn, et al.
(författare)
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IdeS: A Bacterial Proteolytic Enzyme with Therapeutic Potential.
- 2008
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: IdeS, a proteinase from Streptococcus pyogenes, cleaves immunoglobulin (Ig)G antibodies with a unique degree of specificity. Pathogenic IgG antibodies constitute an important clinical problem contributing to the pathogenesis of a number of autoimmune conditions and acute transplant rejection. To be able to effectively remove such antibodies is therefore an important clinical challenge. METHODOLOGY/PRINCIPAL FINDINGS: IdeS was found to specifically and efficiently cleave IgG in human blood in vitro (20 microg of IdeS caused a complete degradation of IgG in one ml of human whole blood in 15 minutes) and to clear IgG from the blood stream of rabbits in vivo (no IgG was detected six hours following an intravenous injection of 5 mg of IdeS) without any side effects. In a mouse model of immune thrombocytopenic purpura (ITP), polyclonal IgG antibodies against platelet surface antigens were used to induce a lethal disease. These profoundly thrombocytopenic animals were treated and cured by a single injection of IdeS. CONCLUSIONS/SIGNIFICANCE: Novel information is provided concerning the IgG-cleaving activity of IdeS in vitro and in vivo. The highly specific and rapid elimination of IgG in vivo, the dramatic effect in a mouse model of ITP, and the lack of side effects in the treated animals, indicate that IdeS could also be used to treat IgG-driven diseases in humans.
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| 68. |
- Johansson, Björn, et al.
(författare)
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The protein expression of Streptococcus pyogenes is significantly influenced by human plasma
- 2005
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Ingår i: Journal of Proteome Research. - Washington : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 4:6, s. 2302-2311
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Tidskriftsartikel (refereegranskat)abstract
- During the courser of infection, the common human pathogen Streptococcus pyogenes encounters plasma. We show that plasma causes S. pyogenes to rapidly remodel its cellular metabolism and virulence pathways. We also identified a variant of the major virulence factor, M1 protein, lacking 13 amino acids at the NH2-terminus in bacteria grown with plasma. The pronounced effect of plasma on protein expression, suggests this is an important adaptive mechanism with implications for S. pyogenes pathogenicity.
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| 69. |
- Johansson, Maria U, et al.
(författare)
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Differences in Backbone Dynamics of Two Homologous Bacterial Albumin-binding Modules: Implications for Binding Specificity and Bacterial Adaptation.
- 2002
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Ingår i: Journal of Molecular Biology. - : Elsevier BV. - 1089-8638 .- 0022-2836. ; 316:5, s. 1083-1099
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Tidskriftsartikel (refereegranskat)abstract
- Proteins G and PAB are bacterial albumin-binding proteins expressed at the surface of group C and G streptococci and Peptostreptococcus magnus, respectively. Repeated albumin-binding domains, known as GA modules, are found in both proteins. The third GA module of protein G from the group G streptococcal strain G148 (G148-GA3) and the second GA module of protein PAB from P.magnus strain ALB8 (ALB8-GA) exhibit 59% sequence identity and both fold to form three-helix bundle structures that are very stable against thermal denaturation. ALB8-GA binds human serum albumin with higher affinity than G148-GA3, but G148-GA3 shows substantially broader albumin-binding specificity than ALB8-GA. The (15)N nuclear magnetic resonance spin relaxation measurements reported here, show that the two GA modules exhibit mobility on the picosecond-nanosecond time scale in directly corresponding regions (loops and termini). Most residues in G148-GA3 were seen to be involved in conformational exchange processes on the microsecond-millisecond time scale, whereas for ALB8-GA such motions were only identified for the beginning of helix 2 and its preceding loop. Furthermore, and more importantly, hydrogen-deuterium exchange and saturation transfer experiments reveal large differences between the two GA modules with respect to motions on the second-hour time scale. The high degree of similarity between the two GA modules with respect to sequence, structure and stability, and the observed differences in dynamics, binding affinity and binding specificity to different albumins, suggest a distinct correlation between dynamics, binding affinity and binding specificity. Finally, it is noteworthy in this context that the module G148-GA3, which has broad albumin-binding specificity, is expressed by group C and G streptococci known to infect all mammalian species, whereas P.magnus with the ALB8-GA module has been isolated only from humans.
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| 70. |
- Johansson, Maria U, et al.
(författare)
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Structure, specificity, and mode of interaction for bacterial albumin-binding modules.
- 2002
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Ingår i: Journal of Biological Chemistry. - 1083-351X .- 0021-9258. ; 277:10, s. 8114-8120
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Tidskriftsartikel (refereegranskat)abstract
- We have determined the solution structure of an albumin binding domain of protein G, a surface protein of group C and G streptococci. We find that it folds into a left handed three-helix bundle similar to the albumin binding domain of protein PAB from Peptostreptococcus magnus. The two domains share 59% sequence identity, are thermally very stable, and bind to the same site on human serum albumin. The albumin binding site, the first determined for this structural motif known as the GA module, comprises residues spanning the first loop to the beginning of the third helix and includes the most conserved region of GA modules. The two GA modules have different affinities for albumin from different species, and their albumin binding patterns correspond directly to the host specificity of C/G streptococci and P. magnus, respectively. These studies of the evolution, structure, and binding properties of the GA module emphasize the power of bacterial adaptation and underline ecological and medical problems connected with the use of antibiotics.
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