Allelic variants of streptokinase from<i>Streptococcus pyogenes</i>display functional differences in plasminogen activation

McArthur, Jason D.; McKay, Fiona C.; Ramachandran, Vidiya; Shyam, Priya; Cork, Amanda J.; Sanderson-Smith, Martina L.; Cole, Jason N.; Ringdahl, Ulrika; Sjöbring, Ulf; Ranson, Marie; Walker, Mark J.

doi:10.1096/fj.08-109348

Cited by 54 publications

(97 citation statements)

References 44 publications

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“…Genes with a differential presence or absence among tissue-tropic strains include cpa (encoding a type I collagen binding protein) (168), prtF1 (encoding the fibronectin binding protein PrtF1) (169), sof (encoding serum opacity factor, which contains a fibronectin binding domain) (170,171), and prtF2 (encoding the fibronectin binding protein PrtF2) (172). Loci that form discrete phylogenetic lineages, which can then be associated with tissue-specific emm patterns, include the transcriptional regulators mga (a global regulator of numerous virulence factors) (173), rofA and nra (mutually exclusive transcriptional regulators of the genes in the FCT region) (167), and ska (encoding the plasminogen-activating protein streptokinase) (174,175). While it is conceivable that tissue site preferences for infection in the throat or skin might be explained by the expression and/or regulation of tissue-specific colonization factors such as adhesins, the exact mechanisms responsible for tissue tropism are yet to be fully elucidated.…”

Section: Gas Tissue Tropismmentioning

confidence: 99%

“…Ska is a single-chain, 414-amino-acid protein composed of three distinct domains (333). Phylogenetic studies of the most divergent ska sequences have revealed two main sequence clusters (cluster types 1 and 2), with evidence of smaller subclusters observed in cluster type 2 sequences (cluster types 2a and 2b) (174,175). Ska variants display significant functional differences, with cluster type 2, but not type 1, streptokinase requiring fibrinogen to efficiently activate plasminogen (175).…”

Section: Subversion Of the Plasminogen Activation Systemmentioning

confidence: 99%

“…Phylogenetic studies of the most divergent ska sequences have revealed two main sequence clusters (cluster types 1 and 2), with evidence of smaller subclusters observed in cluster type 2 sequences (cluster types 2a and 2b) (174,175). Ska variants display significant functional differences, with cluster type 2, but not type 1, streptokinase requiring fibrinogen to efficiently activate plasminogen (175). The species specificity of Ska impacts the design and utility of small-animal models of GAS infection (334).…”

Section: Subversion Of the Plasminogen Activation Systemmentioning

confidence: 99%

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Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

et al. 2014

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SUMMARY Streptococcus pyogenes , also known as group A Streptococcus (GAS), causes mild human infections such as pharyngitis and impetigo and serious infections such as necrotizing fasciitis and streptococcal toxic shock syndrome. Furthermore, repeated GAS infections may trigger autoimmune diseases, including acute poststreptococcal glomerulonephritis, acute rheumatic fever, and rheumatic heart disease. Combined, these diseases account for over half a million deaths per year globally. Genomic and molecular analyses have now characterized a large number of GAS virulence determinants, many of which exhibit overlap and redundancy in the processes of adhesion and colonization, innate immune resistance, and the capacity to facilitate tissue barrier degradation and spread within the human host. This improved understanding of the contribution of individual virulence determinants to the disease process has led to the formulation of models of GAS disease progression, which may lead to better treatment and intervention strategies. While GAS remains sensitive to all penicillins and cephalosporins, rising resistance to other antibiotics used in disease treatment is an increasing worldwide concern. Several GAS vaccine formulations that elicit protective immunity in animal models have shown promise in nonhuman primate and early-stage human trials. The development of a safe and efficacious commercial human vaccine for the prophylaxis of GAS disease remains a high priority.

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Section: Gas Tissue Tropismmentioning

confidence: 99%

Section: Subversion Of the Plasminogen Activation Systemmentioning

confidence: 99%

Section: Subversion Of the Plasminogen Activation Systemmentioning

confidence: 99%

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Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

et al. 2014

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“…This can hydrolyze fibrin and promote the spread of GAS through tissues. Streptokinase is an important virulence factor that acts in concert with plasmin(ogen)-binding proteins (Table 1), and the reader is referred to a recent article for further information (388).…”

Section: Virulence Factorsmentioning

confidence: 99%

StreptococcusAdherence and Colonization

Nobbs

Lamont

Jenkinson

2009

Microbiol Mol Biol Rev

552

569

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SUMMARY Streptococci readily colonize mucosal tissues in the nasopharynx; the respiratory, gastrointestinal, and genitourinary tracts; and the skin. Each ecological niche presents a series of challenges to successful colonization with which streptococci have to contend. Some species exist in equilibrium with their host, neither stimulating nor submitting to immune defenses mounted against them. Most are either opportunistic or true pathogens responsible for diseases such as pharyngitis, tooth decay, necrotizing fasciitis, infective endocarditis, and meningitis. Part of the success of streptococci as colonizers is attributable to the spectrum of proteins expressed on their surfaces. Adhesins enable interactions with salivary, serum, and extracellular matrix components; host cells; and other microbes. This is the essential first step to colonization, the development of complex communities, and possible invasion of host tissues. The majority of streptococcal adhesins are anchored to the cell wall via a C-terminal LPxTz motif. Other proteins may be surface anchored through N-terminal lipid modifications, while the mechanism of cell wall associations for others remains unclear. Collectively, these surface-bound proteins provide Streptococcus species with a “coat of many colors,” enabling multiple intimate contacts and interplays between the bacterial cell and the host. In vitro and in vivo studies have demonstrated direct roles for many streptococcal adhesins as colonization or virulence factors, making them attractive targets for therapeutic and preventive strategies against streptococcal infections. There is, therefore, much focus on applying increasingly advanced molecular techniques to determine the precise structures and functions of these proteins, and their regulatory pathways, so that more targeted approaches can be developed.

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“…Out of these nine genes, five were previously described for human S. dysgalactiae subsp. equisimilis: lbp (encoding the adhesion Lmb, a laminin-binding protein) (62), ska (encoding the plasminogen-activating Skastreptokinase A protein) (37), slo (encoding the cytolytic streptolysin O toxin) (54), emm (encoding the M protein), as well as scpA (encoding a C5a peptidase), with the latter two genes acting on the complement pathway of the host, inhibiting bacterial opsonization and phagocytosis (8,20). Both the lbp and scpA genes have been found in human GBS isolates and are usually absent in bovine GBS isolates (14).…”

mentioning

confidence: 99%

Virulence Gene Pool Detected in Bovine Group C Streptococcus dysgalactiae subsp. dysgalactiae Isolates by Use of a Group A S. pyogenes Virulence Microarray

et al. 2011

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A custom-designed microarray containing 220 virulence genes of Streptococcus pyogenes (group A Streptococcus [GAS]) was used to test group C Streptococcus dysgalactiae subsp. dysgalactiae (GCS) field strains causing bovine mastitis and group C or group G Streptococcus dysgalactiae subsp. equisimilis (GCS/GGS) isolates from human infections, with the latter being used for comparative purposes, for the presence of virulence genes. All bovine and all human isolates carried a fraction of the 220 genes (23% and 39%, respectively). The virulence genes encoding streptolysin S, glyceraldehyde-3-phosphate dehydrogenase, the plasminogen-binding M-like protein PAM, and the collagen-like protein SclB were detected in the majority of both bovine and human isolates (94 to 100%). Virulence factors, usually carried by human beta-hemolytic streptococcal pathogens, such as streptokinase, laminin-binding protein, and the C5a peptidase precursor, were detected in all human isolates but not in bovine isolates. Additionally, GAS bacteriophage-associated virulence genes encoding superantigens, DNase, and/or streptodornase were detected in bovine isolates (72%) but not in the human isolates. Determinants located in non-bacteriophage-related mobile elements, such as the gene encoding R28, were detected in all bovine and human isolates. Several virulence genes, including genes of bacteriophage origin, were shown to be expressed by reverse transcriptase PCR (RT-PCR). Phylogenetic analysis of superantigen gene sequences revealed a high level (>98%) of identity among genes of bovine GCS, of the horse pathogen Streptococcus equi subsp. equi, and of the human pathogen GAS. Our findings indicate that alphahemolytic bovine GCS, an important mastitis pathogen and considered to be a nonhuman pathogen, carries important virulence factors responsible for virulence and pathogenesis in humans.

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Allelic variants of streptokinase fromStreptococcus pyogenesdisplay functional differences in plasminogen activation

Cited by 54 publications

References 44 publications

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

Disease Manifestations and Pathogenic Mechanisms of Group A Streptococcus

StreptococcusAdherence and Colonization

Virulence Gene Pool Detected in Bovine Group C Streptococcus dysgalactiae subsp. dysgalactiae Isolates by Use of a Group A S. pyogenes Virulence Microarray

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