Plasminogen Is a Critical Host Pathogenicity Factor for Group A Streptococcal Infection

Sun, Hongmin; Ringdahl, Ulrika; Homeister, Jonathon W.; Fay, William P.; Engleberg, N. Cary; Yang, Angela; Rozek, Laura S.; Wang, Xixi; Sjöbring, Ulf; Ginsburg, David

doi:10.1126/science.1101245

Cited by 353 publications

(365 citation statements)

References 24 publications

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“…This natural resistance of mice to severe GAS sepsis can be overcome by the use of high infectious doses, less resistant strains or transgenic mice carrying human HLA class II 18 or human plasminogen. 45,46 Despite this, successful attempts were made with standard inbred mouse lines, for example, BALB/c, C3H/HeN and CBA/J, C57BL/10 17 and DBA/2 and C57BL/6 (Kansal and Kotb, personal communication); whereas these studies were quite informative, conventional mouse models are limited in their genetic pool, and thus one may miss important genotype-trait relations. Our choice was thus to use one of the genetically diversified mouse reference populations generated by the international Complex Trait Consortium (CTC).…”

Section: Discussionmentioning

confidence: 99%

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

et al. 2007

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Variation in responses to pathogens is influenced by exposure history, environment and the host's genetic status. We recently demonstrated that human leukocyte antigen class II allelic differences are a major determinant of the severity of invasive group A streptococcal (GAS) sepsis in humans. While in-depth controlled molecular studies on populations of genetically wellcharacterized humans are not feasible, it is now possible to exploit genetically diverse panels of recombinant inbred BXD mice to define genetic and environmental risk factors. Our goal in this study was to standardize the model and identify genetic and nongenetic covariates influencing invasive infection outcomes. Despite having common ancestors, the various BXD strains (n strains ¼ 33, n individuals ¼ 445) showed marked differences in survival. Mice from all strains developed bacteremia but exhibited considerable differences in disease severity, bacterial dissemination and mortality rates. Bacteremia and survival showed the expected negative correlation. Among nongenetic factors, age -but not sex or weight -was a significant predictor of survival (P ¼ 0.0005). To minimize nongenetic variability, we limited further analyses to mice aged 40-120 days and calculated a corrected relative survival index that reflects the number of days an animal survived post-infection normalized to all significant covariates. Genetic background (strain) was the most significant factor determining susceptibility (Pp0.0001), thus underscoring the strong effect of host genetic variation in determining susceptibility to severe GAS sepsis. This model offers powerful unbiased forward genetics to map specific quantitative trait loci and networks of pathways modulating the severity of GAS sepsis.

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Section: Discussionmentioning

confidence: 99%

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

et al. 2007

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“…Just to add to the complexity, it is interesting and perhaps surprising, given the literature on the contribution to bacterial virulence of plasminogen activation to plasmin by bacterial enzymes, possibly via fibrin dissolution (see, for example, refs. [18][19][20], that Plg Ϫ/Ϫ mice were found to be more susceptible to S aureus-induced arthritis than the wild-type controls. When human plasminogen was given intravenously to the Plg Ϫ/Ϫ mice, bacterial clearance was enhanced, and the amount of necrotic tissue in the joint cavity was reduced.…”

Section: The Pa/plasmin System In a Septic Arthritis Modelmentioning

confidence: 99%

“…It might have been expected that there would have been less severe infection in the Plg Ϫ/Ϫ mice (18)(19)(20) and therefore perhaps less arthritis. Whether the intraarticular route of administration rather than the normal route of a systemic infection contributes to these intriguing findings is unknown, as is whether the protective effects of plasmin(ogen) are direct or indirect.…”

Section: The Pa/plasmin System In a Septic Arthritis Modelmentioning

confidence: 99%

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

Hamilton¹

2008

Arthritis & Rheumatism

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“…A mounting body of clinical, epidemiological and experimental evidence suggests an important role for plasminogen activation in GAS virulence (7,8). Plasminogen is a single chain glycoprotein found in plasma and extracellular fluids at concentrations of approximately 2 μM (9).…”

Section: Introductionmentioning

confidence: 99%

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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Plasminogen Is a Critical Host Pathogenicity Factor for Group A Streptococcal Infection

Cited by 353 publications

References 24 publications

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

Susceptibility to severe streptococcal sepsis: use of a large set of isogenic mouse lines to study genetic and environmental factors

Plasminogen activator/plasmin system in arthritis and inflammation: Friend or foe?

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

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