Human fibrinogen bound to Streptococcus pyogenes M protein inhibits complement deposition via the classical pathway

Area of Science:

• Microbiology
• Immunology
• Molecular Biology

Background:

• Pathogenic bacteria interact with host proteins like human fibrinogen (Fg).
• The role of Fg bound to bacterial surface proteins, particularly Streptococcus pyogenes M protein, in host-pathogen interactions is not fully understood.
• M protein is a major virulence factor conferring resistance to phagocytosis.

Purpose of the Study:

• To analyze the role of Fg bound to Streptococcus pyogenes M protein in virulence and host immune evasion.
• To elucidate the mechanism by which M protein-bound Fg confers resistance to phagocytosis.
• To propose a unifying mechanism for how M proteins interfere with innate immunity.

Main Methods:

• Chromosomal mutagenesis to create a mutant lacking the Fg-binding region of M5 protein.
• Phagocytosis assays to assess bacterial resistance.
• Complement deposition studies using the classical pathway.
• Analysis of C3 convertase formation on the bacterial surface.

Main Results:

• A mutant lacking the Fg-binding region of M5 protein was completely susceptible to phagocytosis, indicating Fg's key role in virulence.
• M5-bound Fg blocked complement deposition via the classical pathway by reducing C3 convertase formation on the bacterial surface.
• This Fg-mediated inhibition of complement deposition explains resistance to phagocytosis.

Conclusions:

• Surface-bound Fg has a novel function in bacterial virulence by inhibiting complement deposition.
• M proteins may universally recruit either Fg or C4BP to inhibit classical pathway complement deposition.
• This provides a unifying mechanism for how M proteins evade innate immunity.