Functional dissection of Streptococcus pyogenes M5 protein: the hypervariable region is essential for virulence

Area of Science:

• Microbiology
• Infectious Diseases
• Bacterial Pathogenesis

Background:

• Streptococcus pyogenes M protein is a key virulence factor, inhibiting phagocytosis ex vivo.
• Its in vivo role, particularly concerning different protein regions, remains largely uncharacterized.

Purpose of the Study:

• To investigate the in vivo contribution of distinct M protein regions to Streptococcus pyogenes virulence.
• To elucidate the specific roles of the N-terminal hypervariable region (HVR) and fibrinogen-binding B-repeat region in pathogenesis.

Main Methods:

• Utilized a mouse model of acute invasive infection with the fibrinogen (Fg)-binding M5 protein.
• Conducted mixed infection experiments comparing wild-type bacteria with mutants lacking specific M protein regions (HVR, B-repeats, C-repeats).

Main Results:

• Mutants lacking the HVR or B-repeat region were significantly attenuated in virulence.
• A mutant lacking the conserved C-repeats showed only slight attenuation.
• The HVR was not essential for phagocytosis resistance, suggesting an unknown in vivo function.
• B-repeat mutants were attenuated even in fibrinogen-deficient mice, indicating a potential dual role.

Conclusions:

• Two distinct regions of the M5 protein, the HVR and the B-repeat region, are critical for virulence during early infection stages.
• This study provides the first in vivo evidence for a significant role of the M protein HVR in bacterial pathogenesis.
• The B-repeats likely contribute to virulence through both fibrinogen binding and an additional, yet unidentified, mechanism.