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

Abstract

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.

Full Time Course Kinetics of the Streptokinase-Plasminogen Activation Pathway

“…Concerning the role of SK as a virulence factor in streptococcal infections, generation of Pm is critical for dissemination of the bacteria through tissues by directly cleaving extracellular matrix proteins, indirectly activating metalloproteinases, and dissolving fibrin barriers established in the initial host response to infection (52)(53)(54)(55). The SK-Pg activation mechanism is regulated by fibrinogen and fibrin through a SK⅐Pg⅐fibrin(ogen) ternary complex and by Pg-binding group A streptococcal M-like protein (PAM) that is covalently bound to the bacterial cell wall (46 -50, 53, 54, 56).…”

“…Direct binding of Pm or SK⅐Pg*-generated Pm bound to PAM results in coating of the bacterial surface by proteolytically active PAM⅐Pm complexes that are resistant to inactivation by AP, allowing the bacteria to spread rapidly through fibrin barriers and the extracellular matrix like proteolytic chain saws. Other members of the M protein superfamily lack the Pm-binding motifs, but a subset of them, including M1, bind Fbg specifically through the b-type repeats (53,54,57,58,60). This begins what is called the indirect pathway of Pm generation through formation of the SK⅐Pg*⅐Fbg ternary complex (48,61), which is resistant to inactivation by AP and, we now know, intrinsically assembles with 200-fold higher, subnanomolar affinity compared with SK⅐Pg*.…”

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

“…Several microbial proteins bind Factor H, FHL-1, and also plasminogen. These include Tuf from P. aeruginosa, CRASPs from B. burgdorferi, BpcA from Borrelia parkeri, and M protein from S. pyogenes (11,22,36,51,52). Plasminogen is composed of five kringle domains each of ∼80 aa in size linked to a protease domain.…”

Resistance of Bacteria to the Factors of the Innate Immune System, Mediated by Bacterial Proteases

“…Bacterial to escape this response on plasmin (plasminogen) affect as, the most potent endogenous protease present in the serum. Thus, by affecting the fibrinolysis system, many pathogenic bacteria are easily disseminated and avoid elimination [20]. The spirochete Borrelia burgdorferi, responsible for the development of Lyme disease, change the system of plasmin activators [21].…”