Mouse skin passage of Streptococcus pyogenes results in increased streptokinase expression and activity

Rezcallah, Myrna S.; Boyle, Michael D. P.; Sledjeski, Darren D.

doi:10.1099/mic.0.26826-0

Cited by 27 publications

(27 citation statements)

References 50 publications

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“…Western immunoblotting experiments using anti-SpeB polyclonal sera demonstrated that the cysteine protease SpeB, which is known to degrade streptokinase (33) was not present in supernatants harvested at this phase of growth (data not shown). This was corroborated by Western-immunoblotting performed using anti-streptokinase polyclonal sera as it detected an immunoreactive band ranging from approximately 46 to 49 kDa in culture supernatants for all GAS isolates, including those harbouring a cluster 2 ska allele ( Figure 2B).…”

Section: Activity and Expression Of Streptokinase Allelic Variantsmentioning

confidence: 98%

Allelic variants of streptokinase fromStreptococcus pyogenesdisplay functional differences in plasminogen activation

et al. 2008

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A common mammalian defence mechanism employed to prevent systemic dissemination of invasive bacteria involves occlusion of local microvasculature and encapsulation of bacteria within fibrin networks. Acquisition of plasmin activity at the bacterial cell surface circumvents this defence mechanism allowing invasive disease initiation. To facilitate this process, S. pyogenes secrete streptokinase, a plasminogen activating protein.Streptokinase polymorphism exhibited by S. pyogenes isolates is well characterised. However, the functional differences displayed by these variants and the biological significance of this variation has not been elucidated. Phylogenetic analysis of ska sequences from 28 S. pyogenes isolates revealed two main sequence clusters (clusters 1 and 2). All strains secreted streptokinase as determined by western blotting and were capable of acquiring cell-surface plasmin activity after incubation in human plasma. Whereas culture supernatants from strains containing cluster 1 ska alleles also displayed soluble plasminogen activation activity, supernatants from strains containing cluster 2 ska alleles did not. Furthermore, plasminogen activation activity in culture supernatants from strains containing cluster 2 ska alleles could only be detected when plasminogen was prebound with fibrinogen. This study indicates that variant streptokinase proteins secreted by S. pyogenes isolates display differing plasminogen activation characteristics and may therefore play distinct roles in disease pathogenesis. AbstractA common mammalian defence mechanism employed to prevent systemic dissemination of invasive bacteria involves occlusion of local microvasculature and encapsulation of bacteria within fibrin networks. Acquisition of plasmin activity at the bacterial cell surface circumvents this defence mechanism allowing invasive disease initiation. To facilitate this process, S. pyogenes secrete streptokinase, a plasminogen activating protein. Streptokinase polymorphism exhibited by S. pyogenes isolates is well characterised. However, the functional differences displayed by these variants and the biological significance of this variation has not been elucidated. Phylogenetic analysis of ska sequences from 28 S. pyogenes isolates revealed two main sequence clusters (clusters 1 and 2). All strains secreted streptokinase as determined by western blotting and were capable of acquiring cell-surface plasmin activity after incubation in human plasma. Whereas culture supernatants from strains containing cluster 1 ska alleles also displayed soluble plasminogen activation activity, supernatants from strains containing cluster 2 ska alleles did not. Furthermore, plasminogen activation activity in culture supernatants from strains containing cluster 2 ska alleles could only be detected when plasminogen was pre-bound with fibrinogen. This study indicates that variant streptokinase proteins secreted by S. pyogenes isolates display differing plasminogen activation characteristics and may therefore play distinct roles in...

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Section: Activity and Expression Of Streptokinase Allelic Variantsmentioning

confidence: 98%

Allelic variants of streptokinase fromStreptococcus pyogenesdisplay functional differences in plasminogen activation

et al. 2008

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“…Accordingly, we investigated the functional effect of CovS on SK2b production in AP53 cells through examination of the activation of hPg by dialyzed whole cell culture supernatants of mid-log phase (A 600 nm ϳ0.6) GAS cells. E64 (28 M) was maintained in the inoculated cultures and in assays to inhibit the known degradation of SK by aSpeB (47). The data obtained show that AP53 cells mutated to display the WT-CovRS system, viz.…”

Section: Effect Of the Truncation Mutant Of Covs (Covs M ) On Functiomentioning

confidence: 99%

A Natural Inactivating Mutation in the CovS Component of the CovRS Regulatory Operon in a Pattern D Streptococcal pyogenes Strain Influences Virulence-associated Genes*

Zhong

Zhang

Agrahari

et al. 2013

Journal of Biological Chemistry

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Background:The two-component CovRS system is a GAS virulence gene regulator. Results: A natural inactivating mutation has been found in CovS in a skin-invasive GAS strain, potentially affecting expression of key virulence genes. Conclusion: The mutation in CovS showed substantial effects on regulation of virulence genes. Significance: Expression of genes critical to GAS virulence can reveal reasons why specific strains of GAS are effective tissue specialists.

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“…SpeB is known to cleave host proteins including extracellular matrix components, cytokine precursors, immunoglobulins and antimicrobial peptides (1,6,7), and has been shown to play an important role in establishing localized skin infections (8). SpeB also degrades GAS virulence factors including the cell wall-associated fibrinogen-binding anti-phagocytic M1 protein (9,10), various superantigens (11,12), and the secreted plasminogen activator streptokinase (13).…”

Section: Epidemic Invasive Group a Streptococcus (Gas S Pyogenes) Dmentioning

confidence: 99%

Trigger for group A streptococcal M1T1 invasive disease

Cole¹,

McArthur²,

McKay³

et al. 2006

FASEB j.

139

162

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The globally disseminated Streptococcus pyogenes M1T1 clone causes a number of highly invasive human diseases. The transition from local to systemic infection occurs by an unknown mechanism; however invasive M1T1 clinical isolates are known to express significantly less cysteine protease SpeB than M1T1 isolates from local infections. Here, we show that in comparison to the M1T1 strain 5448, the isogenic mutant ∆speB accumulated 75-fold more human plasmin activity on the bacterial surface following incubation in human plasma. Human plasminogen was an absolute requirement for M1T1 strain 5448 virulence following subcutaneous infection of humanized plasminogen transgenic mice. S. pyogenes M1T1 isolates from the blood of infected humanized plasminogen transgenic mice expressed reduced levels of SpeB in comparison with the parental 5448 used as inoculum. We propose that the human plasminogen system plays a critical role in group A streptococcal M1T1 systemic disease initiation. SpeB is required for S. pyogenes M1T1 survival at the site of local infection, however, SpeB also disrupts the interaction of S. pyogenes M1T1 with the human plasminogen activation system. Loss of SpeB activity in a sub-population of S. pyogenes M1T1 at the site of infection results in accumulation of surface plasmin activity thus triggering systemic spread. ABSTRACT The globally disseminated Streptococcus pyogenes M1T1 clone causes a number of highly invasive human diseases. The transition from local to systemic infection occurs by an unknown mechanism; however invasive M1T1 clinical isolates are known to express significantly less cysteine protease SpeB than M1T1 isolates from local infections. Here, we show that in comparison to the M1T1 strain 5448, the isogenic mutant ∆speB accumulated 75-fold more human plasmin activity on the bacterial surface following incubation in human plasma. Human plasminogen was an absolute requirement for M1T1 strain 5448 virulence following subcutaneous infection of humanized plasminogen transgenic mice. S. pyogenes M1T1 isolates from the blood of infected humanized plasminogen transgenic mice expressed reduced levels of SpeB in comparison with the parental 5448 used as inoculum. We propose that the human plasminogen system plays a critical role in group A streptococcal M1T1 systemic disease initiation. SpeB is required for S. pyogenes M1T1 survival at the site of local infection, however, SpeB also disrupts the interaction of S. pyogenes M1T1 with the human plasminogen activation system. Loss of SpeB activity in a sub-population of S. pyogenes M1T1 at the site of infection results in accumulation of surface plasmin activity thus triggering systemic spread.

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Mouse skin passage of Streptococcus pyogenes results in increased streptokinase expression and activity

Cited by 27 publications

References 50 publications

Allelic variants of streptokinase fromStreptococcus pyogenesdisplay functional differences in plasminogen activation

Allelic variants of streptokinase fromStreptococcus pyogenesdisplay functional differences in plasminogen activation

A Natural Inactivating Mutation in the CovS Component of the CovRS Regulatory Operon in a Pattern D Streptococcal pyogenes Strain Influences Virulence-associated Genes*

Trigger for group A streptococcal M1T1 invasive disease

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