| 1. |
- Khil, J, et al.
(författare)
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Plasminogen enhances virulence of group A streptococci by streptokinase-dependent and streptokinase-independent mechanisms
- 2003
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Ingår i: Journal of Infectious Diseases. - : Oxford University Press (OUP). - 1537-6613 .- 0022-1899. ; 188:4, s. 497-505
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between host plasminogen (Plg) and streptokinase (SK) secreted by group A streptococci ( GAS) have been hypothesized to promote bacterial invasion of tissues. The virulence of GAS strain UMAA2616, after being subcutaneously inoculated into mice, was studied. Skin lesions and mortality were observed after inoculation of 7 x 10(6) cfu. Coadministration of human Plg with UMAA2616 markedly increased virulence. SK-deficient UMAA2616 (UMAA2616-SK-) was generated. Mean skin-lesion area and mortality, after bacterial inoculation (3 x 10(5) cfu), were significantly greater with UMAA2616 in the presence of human Plg than with UMAA2616-SK- in the presence of human Plg (P = .0001). Human Plg also enhanced UMAA2616-SK- vir ulence. Exogenous human Plg enhanced the virulence of MGAS166, a human clinical isolate. These findings suggest that SK-Plg interactions are an important determinant of GAS invasiveness in vivo and that both SK and host Plg activators appear to promote virulence of GAS by catalyzing plasmin formation.
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| 2. |
- Ringdahl, Ulrika, et al.
(författare)
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A role for the fibrinogen-binding regions of streptococcal M proteins in phagocytosis resistance
- 2000
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Ingår i: Molecular Microbiology. - : Wiley. - 1365-2958 .- 0950-382X. ; 37:6, s. 1318-1326
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Tidskriftsartikel (refereegranskat)abstract
- All virulent group A streptococcal isolates bind fibrinogen, a property that is closely linked to expression of type-specific antiphagocytic surface molecules designated M proteins. Here we show that although the M proteins from two different strains, M1 and M5, both bind fibrinogen with high affinity, they interact with different regions in the ligand. Moreover, mapping experiments demonstrated that the fibrinogen-binding regions in the M1 and M5 proteins are quite dissimilar at the amino acid sequence level and that they bind to different regions in the plasma protein. In spite of these differences, the fibrinogen-binding regions of M1 and M5 could both be shown to contribute to streptococcal survival in human blood, providing evidence for the distinct function of a plasma protein interaction in bacterial pathogenesis.
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| 3. |
- Ringdahl, Ulrika
(författare)
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Streptococcus pyogenes and its interactions with the human host
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- We have found that a set of group A streptococcal strains, primarily associated with skin infections, express surface-associated M proteins that bind plasminogen and plasmin with high affinity. The binding is mediated by a common 13 amino acid internal repeated sequence located in the NH2-terminal surface-exposed portion of these M proteins. It could be demonstrated that plasminogen, absorbed by the bacteria when grown in plasma, could be activated by exogenous and endogenous streptokinase, a potent plasminogen activating protein that is secreted by group A streptococci, thereby providing the bacteria with a surface-associated enzyme that could act on fibrin films or other tissue barriers in the infected host. While only a subset of these bacteria bind plasminogen, almost all group A streptococcal strains bind fibrinogen. It is known that this property is coupled to members of the M protein family. We first identified the fibrinogen-binding region in the type M1 and M5 proteins and then generated an isogenic strain expressing an M5 protein lacking the fibrinogen-binding region. This strain had lost the ability to resist phagocytosis in human blood, a feature that is characteristic for group A streptococci. Furthermore, streptococcal mutants expressing versions of the fibrinogen non-binding M4 protein grafted with the fibrinogen-binding regions from M1 or M5 were generated. The manipulation converted these strains from phagocytosis sensitive to phagocytosis resistant, demonstrating the importance of the fibrinogen-binding capacity for bacterial survival. The ability to bind fibrinogen also gives the bacteria the ability to interact with platelets. Fibrinogen serves as a link between the bacteria and the platelet and the subsequent binding of antibodies directed against the bacteria to the FcgRIIa receptor can induce platelet activation and aggregation, a property that may contribute to acute complications in severe group A streptococcal infection.
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| 4. |
- Sjöbring, Ulf, et al.
(författare)
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Analysis of plasminogen-binding M proteins of Streptococcus pyogenes.
- 2000
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Ingår i: Methods. - 1095-9130. ; 21:2, s. 143-150
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Tidskriftsartikel (refereegranskat)abstract
- Group A streptococci are common human pathogens that cause a variety of infections. They express M proteins which are important cell wall-bound type-specific virulence factors. We have found that a set of strains, associated primarily with skin infections, express M proteins that bind plasminogen and plasmin with high affinity. The binding is mediated by a 13-amino-acid internal repeated sequence located in the N-terminal surface-exposed portion of these M proteins. This sequence binds to kringle 2 in plasminogen, a domain that is not involved in the interaction with streptokinase, a potent group A streptococcal activator of plasminogen. It could be demonstrated that plasminogen, absorbed from plasma by growing group A streptococci expressing the plasminogen-binding M proteins, could be activated by exogenous and endogenous streptokinase, thereby providing the bacteria with a surface-associated enzyme that could act on the tissue barriers in the infected host.
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| 5. |
- Sjöbring, Ulf, et al.
(författare)
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Induction of platelet thrombi by bacteria and antibodies
- 2002
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 100:13, s. 4470-4477
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Tidskriftsartikel (refereegranskat)abstract
- We have characterized 2 distinct mechanisms through which infectious agents may promote platelet adhesion and thrombus formation in flowing blood, thus contributing to the progression of disease. In one case, the process initiates when the integrin alpha(IIb)beta(3) mediates platelet arrest onto immobilized bacterial constituents that have bound plasma fibrinogen. If blood contains antibodies against the bacteria, immunoglobulin (Ig) G may cluster on the same surface and activate adherent platelets through the FcgammaRIIA receptor, leading to thrombus growth. As an alternative, bacteria that cannot bind fibrinogen may attach to substrates, such as immobilized plasma proteins or components of the extracellular matrix, which also support platelet adhesion. As a result of this colocalization, IgG bound to bacteria can activate neighboring platelets and induce thrombus growth regard-less of their ability to initiate platelet-surface contact. Our results demonstrate that intrinsic constituents of infectious agents and host proteins play distinct but complementary roles in recruiting platelets into thrombi, possibly contributing to complications of acute and chronic infections.
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| 6. |
- Sun, HM, et al.
(författare)
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Plasminogen is a critical host pathogenicity factor for group A streptococcal infection
- 2004
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 305:5688, s. 1283-1286
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Tidskriftsartikel (refereegranskat)abstract
- Group A streptococci, a common human pathogen, secrete streptokinase, which activates the host's blood clot-dissolving protein, plasminogen. Streptokinase is highly specific for human plasminogen, exhibiting little or no activity against other mammalian species, including mouse. Here, a transgene expressing human plasminogen markedly increased mortality in mice infected with streptococci, and this susceptibility was dependent on bacterial streptokinase expression. Thus, streptokinase is a key pathogenicity factor and the primary determinant of host species specificity for group A streptococcal infection. In addition, local fibrin clot formation may be implicated in host defense against microbial pathogens.
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