Plasminogen Enhances Virulence of Group A Streptococci by Streptokinase‐Dependent and Streptokinase‐Independent Mechanisms

Khil, Jinmo; Im, Michael M.; Heath, Andrew; Ringdahl, Ulrika; Mundada, Lakshmi; Engleberg, N. Cary; Fay, William P.

doi:10.1086/377100

Cited by 56 publications

(49 citation statements)

References 27 publications

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“…These observations suggest that, for PAM-positive S. pyogenes strains, the specific interaction between human plasminogen kringle 2 domain, subcluster 2b streptokinase and plasminogen binding M proteins provides selection pressure for the co-inheritance of these GAS virulence factors (8,11). A number of PAM-negative GAS strains, including GAS serotype M1T1, also demonstrate human plasminogen dependent virulence (7,26,40) We therefore hypothesise that PAMpositive and PAM-negative GAS strains employ differing strategies for surface plasminogen acquisition and activation. For PAM-negative isolates, the formation of a trimolecular complex of streptokinase, plasminogen and fibrinogen, bound to the GAS cell surface via fibrinogen receptors or the plasminogen receptors α-enolase and GAPDH may represent an alternative human plasminogen-dependent virulence pathway employed by this strain set (11,13,34,41).…”

Section: Discussionmentioning

confidence: 92%

M protein‐mediated plasminogen binding is essential for the virulence of an invasiveStreptococcus pyogenesisolate

Sanderson-Smith¹,

Dinkla²,

Cole³

et al. 2008

FASEB j.

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MJ, M protein mediated plasminogen binding is essential for the virulence of an invasive Streptococcus pyogenes isolate, The FASEB Journal, 22(8), 2008, 2715-2722 M protein mediated plasminogen binding is essential for the virulence of an invasive Streptococcus pyogenes isolate AbstractThe human protease plasmin plays a crucial role in the capacity of the group A streptococcus (Streptococus pyogenes; GAS) to initiate invasive disease. The GAS strain NS88.2 was isolated from a case of bacteremia from the Northern Territory of Australia, a region with high rates of GAS invasive disease. Mutagenesis of the NS88.2 plasminogen binding M protein Prp was undertaken to examine the contribution of plasminogen binding and cell surface plasmin acquisition to virulence. The isogenic mutant NS88.2prp was engineered whereby four amino acid residues critical for plasminogen binding were converted to alanine codons in the GAS genome sequence. The mutated residues were reverse complemented to the wildtype sequence to construct GAS strain NS88.2prpRC. In comparison to NS88.2 and NS88.2prpRC, the NS88.2prp mutant exhibited significantly reduced ability to bind human plasminogen and accumulate cell surface plasmin activity during growth in human plasma. Utilising a humanised plasminogen mouse model of invasive infection, we demonstrate that the capacity to bind plasminogen and accumulate surface plasmin activity plays an essential role in GAS virulence. ABSTRACTThe human protease plasmin plays a crucial role in the capacity of the group A streptococcus (Streptococus pyogenes; GAS) to initiate invasive disease. The GAS strain NS88.2 was isolated from a case of bacteremia from the Northern Territory of Australia, a region with high rates of GAS invasive disease. Mutagenesis of the NS88.2 plasminogen binding M protein Prp was undertaken to examine the contribution of plasminogen binding and cell surface plasmin acquisition to virulence.The isogenic mutant NS88.2prp was engineered whereby four amino acid residues critical for plasminogen binding were converted to alanine codons in the GAS genome sequence. The mutated residues were reverse complemented to the wildtype sequence to construct GAS strain NS88.2prpRC. In comparison to NS88.2 and NS88.2prpRC, the NS88.2prp mutant exhibited significantly reduced ability to bind human plasminogen and accumulate cell surface plasmin activity during growth in human plasma. Utilising a humanised plasminogen mouse model of invasive infection, we demonstrate that the capacity to bind plasminogen and accumulate surface plasmin activity plays an essential role in GAS virulence.

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Section: Discussionmentioning

confidence: 92%

M protein‐mediated plasminogen binding is essential for the virulence of an invasiveStreptococcus pyogenesisolate

Sanderson-Smith¹,

Dinkla²,

Cole³

et al. 2008

FASEB j.

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“…Bound plasminogen interacts with GAS streptokinase to generate a bacterial-bound, serine protease-designated plasmin. 86 GAS surface-localized plasmin has been implicated in GAS dissemination. 3,41,74 -86 Statistically higher expression of ska transcripts in the ⌬covR mutant likely contributed to lesion size differences between mutant and WT.…”

Section: Org)mentioning

confidence: 99%

Analysis of the Transcriptome of Group A Streptococcus in Mouse Soft Tissue Infection

Graham

Virtaneva

Porcella

et al. 2006

The American Journal of Pathology

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Molecular mechanisms mediating group A Streptococcus (GAS)-host interactions remain poorly understood but are crucial for diagnostic, therapeutic, and vaccine development. An optimized high-density microarray was used to analyze the transcriptome of GAS during experimental mouse soft tissue infection. The transcriptome of a wild-type serotype M1 GAS strain and an isogenic transcriptional regulator knockout mutant (covR) also were compared. Array datasets were verified by quantitative real-time reverse transcriptase-polymerase chain reaction and in situ immunohistochemistry. The results unambiguously demonstrate that coordinated expression of proven and putative GAS virulence factors is directed toward overwhelming innate host defenses leading to severe cellular damage. We also identified adaptive metabolic responses triggered by nutrient signals and hypoxic/acidic conditions in the host, likely facilitating pathogen persistence and proliferation in soft tissues. Key discoveries included that oxidative stress genes, virulence genes, genes related to amino acid and maltodextrin utilization, and several two-component transcriptional regulators were highly expressed in vivo. This study is the first global analysis of the GAS transcriptome during invasive infection. Coupled with parallel analysis of the covR mutant strain, novel insights have been made into the regulation of GAS virulence in vivo, resulting in new avenues for targeted therapeutic and vaccine research.

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“…SK contributes to streptococcal virulence by generating plasmin, which leads to bacterial spread from a primary focus of infection by causing fibrinolysis and degradation of extracellular matrix and basement membrane components (6,16). Plasmin also induces inflammation via complement activation, which may play a role in postinfectious diseases, such as glomerulonephritis (12).…”

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confidence: 99%

Structural Diversity of Streptokinase and Activation of Human Plasminogen

Lizano

Johnston

2005

Infect Immun

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The ␤ domain of streptokinase is required for plasminogen activation and contains a region of sequence diversity associated with infection and disease in group A streptococci. We report that mutagenesis of this polymorphic region does not alter plasminogen activation, which suggests an alternative function for this molecular motif in streptococcal disease.Streptokinase (SK) is a plasminogen activator secreted by group A, C, and G streptococci. SK contributes to streptococcal virulence by generating plasmin, which leads to bacterial spread from a primary focus of infection by causing fibrinolysis and degradation of extracellular matrix and basement membrane components (6, 16). Plasmin also induces inflammation via complement activation, which may play a role in postinfectious diseases, such as glomerulonephritis (12).The extent to which SK is involved in streptococcal pathogenesis may depend on structural differences among SKs. SK is a 414-amino-acid (aa) protein composed of three structural domains: ␣ (aa 1 to 150), ␤ (aa 151 to 287), and ␥ (aa 288 to 414) (19). The highly conserved (Ն85% sequence identity) ␣ and ␥ domains provide most of the contact sites with the plasmin moiety (2, 19) and exhibit a synergistic effect on plasminogen activation (9). The ␤ domain provides no direct contact sites with the plasmin active-site moiety, yet it is required to dock plasminogen via a kringle-binding surface-exposed hairpin loop (termed the 250-loop) between residues 251 and 262 ( Fig. 1A) (1, 18). In contrast, a region between amino acids 144 and 218 which spans the second structural loop of the ␤ domain (170-loop) (Fig. 1A) is the major focus of sequence heterogeneity (4), yet its function is unknown. The side chains of nonconserved amino acids within this heterogenous loop are oriented towards the surface, away from the side that faces the plasmin moiety of the activator complex (18).This suggests that SK polymorphism may not be directly engaged in plasminogen binding and activation but instead may determine biological properties related to disease. Previous studies have linked sequence patterns within this polymorphic motif to specific strains of group A streptococci (GAS) that cause acute poststreptococcal glomerulonephritis (APSGN) (10). Also, phylogenetic analysis of ␤-domain sequences reveals a strong linkage disequilibrium (P Ͻ Ͻ 0.01) with plasminogen-binding group A streptococcal M protein (PAM) in strains that exhibit tissue tropism to the skin (5). Considering the fact that both SK and PAM cooperate to enhance streptococcal virulence through plasminogen activation (15), the specific association between ␤-domain polymorphism and tissue tropism further supports a role of this motif in disease.Despite these associations, the biological significance of sequence polymorphism in SK remains unknown. Studies on SK structure and function have focused entirely on therapeutic SK from a nonpathogenic group C streptococcus and have not considered the role of sequence polymorphism of the ␤ domain on plasminogen activation...

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Plasminogen Enhances Virulence of Group A Streptococci by Streptokinase‐Dependent and Streptokinase‐Independent Mechanisms

Cited by 56 publications

References 27 publications

M protein‐mediated plasminogen binding is essential for the virulence of an invasiveStreptococcus pyogenesisolate

M protein‐mediated plasminogen binding is essential for the virulence of an invasiveStreptococcus pyogenesisolate

Analysis of the Transcriptome of Group A Streptococcus in Mouse Soft Tissue Infection

Structural Diversity of Streptokinase and Activation of Human Plasminogen

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