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Most invasive bacterial infections are caused by species that more commonly colonize the human host with minimal symptoms. Although phenotypic or genetic correlates underlying a bacterium's shift to enhanced virulence have been studied, the in vivo selection pressures governing such shifts are poorly understood. The globally disseminated M1T1 clone of group A Streptococcus (GAS) is linked with the rare but life-threatening syndromes of necrotizing fasciitis and toxic shock syndrome. Mutations in the GAS control of virulence regulatory sensor kinase (covRS) operon are associated with severe invasive disease, abolishing expression of a broad-spectrum cysteine protease (SpeB) and allowing the recruitment and activation of host plasminogen on the bacterial surface. Here we describe how bacteriophage-encoded GAS DNase (Sda1), which facilitates the pathogen's escape from neutrophil extracellular traps, serves as a selective force for covRS mutation. The results provide a paradigm whereby natural selection exerted by the innate immune system generates hypervirulent bacterial variants with increased risk of systemic dissemination., Author(s): Mark J Walker (corresponding author) [1]; Andrew Hollands [1]; Martina L Sanderson-Smith [1]; Jason N Cole [1]; Joshua K Kirk [1]; Anna Henningham [1]; Jason D McArthur [1]; Katrin [...]

The migration of the human pathogen Streptococcus pyogenes (group A streptococcus) from localized to deep tissue sites may result in severe invasive disease, and sequestration of the host zymogen plasminogen appears crucial for virulence. Here, we describe a novel plasminogen-binding M protein, the plasminogen-binding group A streptococcal M protein (PAM)-related protein (Prp). Prp is phylogenetically distinct from previously described plasminogen-binding M proteins of group A, C, and G streptococci. While competition experiments indicate that Prp binds plasminogen with a lower affinity than PAM (50% effective concentration = 0.34 [micro]M), Prp nonetheless binds plasminogen with high affinity and at physiologically relevant concentrations of plasminogen ([K.sub.d] = 7.8 nM). Site-directed mutagenesis of the putative plasminogen binding site indicates that unlike the majority of plasminogen receptors, Prp does not interact with plasminogen exclusively via lysine residues. Mutagenesis to alanine of lysine residues [Lys.sup.96] and [Lys.sup.101] reduced but did not abrogate plasminogen binding by Prp. Plasminogen binding was abolished only with the additional mutagenesis of [Arg.sup.107] and [His.sup.108] to alanine. Furthermore, mutagenesis of [Arg.sup.107] and [His.sup.108] abolished plasminogen binding by Prp despite the presence of [Lys.sup.96] and [Lys.sup.101] in the binding site. Thus, binding to plasminogen via arginine and histidine residues appears to be a conserved mechanism among plasminogen-binding M proteins.

Multiple species of bacteria are able to sequester the host zymogen plasminogen to the cell surface. Once localised to the bacterial surface, plasminogen can act as a cofactor in adhesion, or, following activation to plasmin, provide a source of potent proteolytic activity. Numerous bacterial plasminogen receptors have been identified, and the mechanisms by which they interact with plasminogen are diverse. Here we provide an overview of bacterial plasminogen receptors and discuss the diverse role bacterial plasminogen acquisition plays in the relationship between bacteria and the host., 1. Introduction Recruitment of plasminogen to the bacterial cell surface is emerging as a central theme in host/pathogen interactions. The glycoprotein plasminogen is found in plasma and extracellular fluids at [...]