Coiled-coil irregularities of the M1 protein structure promote M1-fibrinogen interaction and influence group A

Satoshi Uchiyama1, Federica Andreoni, Claudia Zürcher

  • 1Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Rämistr 100, 8091 Zürich, Switzerland.

Journal of Molecular Medicine (Berlin, Germany)
|February 28, 2013
PubMed

Insights

Altering the Group A Streptococcus M1 protein structure or blocking its interaction with fibrinogen significantly reduces bacterial virulence. This finding suggests new therapeutic strategies for invasive Group A Streptococcus infections.

Area of Science:

  • Microbiology
  • Infectious Diseases
  • Structural Biology

Background:

  • Group A Streptococcus (GAS) is a significant human pathogen.
  • The GAS M1 protein is a key virulence factor enhancing invasiveness and immune evasion.
  • M1 protein's coiled-coil structure, including B-repeats, mediates fibrinogen binding.

Purpose of the Study:

  • To investigate the role of M1 protein's coiled-coil irregularities in full-length M1 virulence.
  • To assess the impact of modulating M1-fibrinogen interactions on GAS virulence.
  • To explore novel therapeutic approaches targeting M1-fibrinogen interactions.

Main Methods:

  • Studied full-length M1 and M1 expressed on live GAS.
  • Assessed GAS adherence and invasion of human endothelial cells.
  • Evaluated GAS killing by whole blood and neutrophils.
  • Tested GAS virulence in a murine necrotising fasciitis model.
  • Investigated the effect of fibrinogen concentration and fragment D on GAS virulence.

Main Results:

  • Altering M1 structure or removing fibrinogen reduced GAS virulence.
  • GAS expressing M1 exhibited impaired adherence, invasion, and increased susceptibility to immune clearance.
  • M1-mediated virulence was dependent on fibrinogen concentration.
  • Blocking M1-fibrinogen interactions with fragment D reduced GAS virulence in vitro and in vivo.

Conclusions:

  • M1-fibrinogen interactions are critical for GAS virulence.
  • Modulating these interactions offers potential complementary therapeutic strategies for invasive GAS infections.

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