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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Background: Dissemination of Pattern D strains of S. pyogenes depends on a functional human fibrinolytic system. Results: hPg binding domains of PAM, when transferred to unrelated M-proteins, up-regulates hPg binding and activation. Conclusion:The nature of the streptokinase and the M-protein influence GAS virulence. Significance: In vitro studies indicate pathways for GAS to gain hypervirulence by gene transfer of small functional domains.

The binding of human plasminogen (hPg) to the surface of the human pathogen group A (GAS) and subsequent hPg activation to the protease plasmin generate a proteolytic surface that GAS employs to circumvent host innate immunity. Direct high-affinity binding of hPg/plasmin to pattern D GAS is fully recapitulated by the hPg kringle 2 domain (K2) and a short internal peptide region (a1a2) of a specific subtype of bacterial surface M protein, present in all GAS pattern D strains. To better understand the nature of this binding, critical to the virulence of many GAS skin-tropic strains, we used high-resolution NMR to define the interaction of recombinant K2 with recombinant a1a2 (VKK38) of the M protein from GAS isolate NS455. We found a 2:1 (m/m) binding stoichiometry of K2/VKK38, with the lysine-binding sites of two K2 domains anchored to two regions of monomeric VKK38. The K2/VKK38 binding altered the VKK38 secondary structure from a helical apo-peptide with a flexible center to an end-to-end K2-bound α-helix. The K2 residues occupied opposite faces of this helix, an arrangement that minimized steric clashing of K2 We conclude that VKK38 provides two conformational lysine isosteres that each interact with the lysine-binding sites in K2 Further, the adoption of an α-helix by VKK38 upon binding to K2 sterically optimizes the side chains of VKK38 for maximal binding to K2 and minimizes steric overlap between the K2 domains. The mechanism for hPg/M protein binding uncovered here may facilitate targeting of GAS virulence factors for disease management.