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Direct Host Plasminogen Binding to Bacterial Surface M-protein in Pattern D Strains of Streptococcus pyogenes Is

Vishwanatha Chandrahas1, Kristofor Glinton1, Zhong Liang1

  • 1From the W. M. Keck Center for Transgene Research and Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556.

The Journal of Biological Chemistry
|June 14, 2015
PubMed

Insights

Group A Streptococcus virulence is linked to how its streptokinase (SK) variants activate human plasminogen (hPg) and bind plasmin (hPm). Different SK types and M-proteins influence bacterial spread and infection site.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Immunology

Background:

  • Streptokinase (SK) from Group A Streptococcus (GAS) activates human plasminogen (hPg) to plasmin (hPm), aiding bacterial dissemination.
  • SK variants (SK1, SK2a, SK2b) and GAS M-proteins exhibit different binding affinities for hPg and hFg, influencing tropism.
  • SK2b is associated with skin infections and plasminogen-binding M-protein (PAM), while SK2a is linked to nasopharyngeal infections and fibrinogen-binding M-proteins like M1.

Purpose of the Study:

  • To investigate the distinct mechanisms of hPg activation by SK2a and SK2b.
  • To elucidate the role of these SK variants and associated M-proteins in GAS virulence.
  • To understand how different hPg/hPm recognition modes contribute to GAS pathogenesis.

Main Methods:

  • Generation of isogenic chimeric GAS strains expressing different SK and M-protein combinations.
  • In vivo virulence analysis of chimeric GAS strains in a mouse model.
  • Biochemical characterization of hPg activation and hPm binding by GAS.

Main Results:

  • Alterations in SK and M-protein significantly influenced GAS virulence in mice.
  • Disparate activation of hPg by SK2a and SK2b was observed, correlating with different hPm binding capabilities.
  • The interplay between SK variants and coinherited M-proteins dictates the nature of hPg activation and GAS dissemination.

Conclusions:

  • GAS virulence is multifactorial, driven by specific interactions between streptokinase variants and M-proteins.
  • The distinct modes of hPg activation by SK2a and SK2b, coupled with M-protein specificity, explain GAS tropism and pathogenicity.
  • Targeting these streptokinase-M-protein interactions could offer novel therapeutic strategies against GAS infections.
Keywords:
Streptococcuscell surfacecell surface proteinfibrinolysisplasminogentransgenicvirulence factor

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