Human IgG Increases Virulence of Streptococcus pyogenes through Complement Evasion.

Area of Science:

• Microbiology
• Immunology
• Pathogenesis

Background:

• Streptococcus pyogenes causes mild to fatal infections by evading the human immune system.
• The bacterium recruits human proteins like C4b-binding protein (C4BP) and human IgG (hu-IgG) to its surface for immune evasion.

Purpose of the Study:

• To investigate a novel virulence mechanism involving IgG-enhanced C4BP binding to S. pyogenes.
• To understand the role of M proteins and protein H in this interaction.

Main Methods:

• Testing C4BP binding to S. pyogenes strains with and without hu-IgG.
• Investigating the interaction between M proteins, protein H, and C4BP.
• Assessing complement downregulation and bacterial killing.
• Evaluating mortality in hu-C4BP transgenic mice treated with hu-IgG.
• Analyzing human necrotizing fasciitis tissue samples.

Main Results:

• IgG binding significantly enhanced C4BP binding to S. pyogenes strains expressing M proteins.
• Binding of hu-IgG Fc to protein H increased protein H's affinity for C4BP.
• Increased C4BP binding led to greater complement downregulation and reduced bacterial killing.
• Mortality in mice increased with concomitant administration of hu-IgG and hu-C4BP.
• Human necrotizing fasciitis samples showed increased C4BP binding to S. pyogenes in the presence of IgG.

Conclusions:

• Human IgG binding to S. pyogenes, particularly via Fc interaction with M proteins, paradoxically increases bacterial virulence.
• This mechanism enhances C4BP-mediated complement evasion, counteracting IgG's beneficial opsonization effects.
• The findings reveal a novel immune evasion strategy exploited by S. pyogenes.