Abstract
ABSTRACTStreptococcus pyogenes is known to cause both mucosal and systemic infections in humans. In this study, we used a combination of quantitative and structural mass spectrometry techniques to determine the composition and structure of the interaction network formed between human plasma proteins and the surfaces of different S. pyogenes serotypes. Quantitative network analysis revealed that S. pyogenes forms serotype-specific interaction networks that are highly dependent on the domain arrangement of the surface-attached M protein. Subsequent structural mass spectrometry analysis and computational modeling of one of the M proteins, M28, revealed that the network structure changes across different host microenvironments. We report that M28 binds secretory IgA via two separate binding sites with high affinity in saliva. During vascular leakage mimicked by increasing plasma concentrations in saliva, the binding of secretory IgA was replaced by the binding of monomeric IgA and C4b-binding protein (C4BP). This indicates that an upsurge of C4BP in the local microenvironment due to damage to the mucosal membrane drives the binding of C4BP and monomeric IgA to M28. These results suggest that S. pyogenes has evolved to form microenvironment-dependent host-pathogen protein complexes to combat human immune surveillance during both mucosal and systemic infections.IMPORTANCE Streptococcus pyogenes (group A Streptococcus [GAS]), is a human-specific Gram-positive bacterium. Each year, the bacterium affects 700 million people globally, leading to 160,000 deaths. The clinical manifestations of S. pyogenes are diverse, ranging from mild and common infections like tonsillitis and impetigo to life-threatening systemic conditions such as sepsis and necrotizing fasciitis. S. pyogenes expresses multiple virulence factors on its surface to localize and initiate infections in humans. Among all these expressed virulence factors, the M protein is the most important antigen. In this study, we perform an in-depth characterization of the human protein interactions formed around one of the foremost human pathogens. This strategy allowed us to decipher the protein interaction networks around different S. pyogenes strains on a global scale and to compare and visualize how such interactions are mediated by M proteins.
Highlights
Streptococcus pyogenes is known to cause both mucosal and systemic infections in humans
The clustering of the strains in the heat map is based on the Z-score, where the Z-score measures the standard deviation of a protein intensity from the mean intensity of that protein across all strains
Fibrinogen is known to bind to the B repeats of the M protein [10, 15, 20], and C4b-binding protein (C4BP) is known to bind to the hypervariable region (HVR) domain [33,34,35,36,37], confirming that serotype-specific networks are highly dependent on the M protein domain arrangement
Summary
Streptococcus pyogenes is known to cause both mucosal and systemic infections in humans. This indicates that an upsurge of C4BP in the local microenvironment due to damage to the mucosal membrane drives the binding of C4BP and monomeric IgA to M28 These results suggest that S. pyogenes has evolved to form microenvironment-dependent host-pathogen protein complexes to combat human immune surveillance during both mucosal and systemic infections. One prominent example is Streptococcus pyogenes (group A Streptococcus [GAS]), a Gram-positive and beta-hemolytic bacterium This bacterium causes diverse clinical manifestations such as mild and local infections like tonsillitis, impetigo, and erysipelas as well as life-threatening systemic diseases like sepsis, meningitis, and necrotizing fasciitis [2]. S. pyogenes abundantly produces a prominent surface antigen, the M protein, known to enable bacterial invasion into human cells, prevent phagocytosis [4, 5], and promote survival in infected tissues [6, 7]. Clade X includes the E pattern, and clade Y includes the A-C pattern, while pattern D seems to fall into both clades X and Y [14]
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