Abstract
The M protein of Streptococcus pyogenes, a major bacterial virulence factor, has an amino-terminal hypervariable region (HVR) that is a target for type-specific protective antibodies. Intriguingly, the HVR elicits a weak antibody response, indicating that it escapes host immunity by two mechanisms, sequence variability and weak immunogenicity. However, the properties influencing the immunogenicity of regions in an M protein remain poorly understood. Here, we studied the antibody response to different regions of the classical M1 and M5 proteins, in which not only the HVR but also the adjacent fibrinogen-binding B repeat region exhibits extensive sequence divergence. Analysis of antisera from S. pyogenes-infected patients, infected mice, and immunized mice showed that both the HVR and the B repeat region elicited weak antibody responses, while the conserved carboxy-terminal part was immunodominant. Thus, we identified a correlation between sequence variability and weak immunogenicity for M protein regions. A potential explanation for the weak immunogenicity was provided by the demonstration that protease digestion selectively eliminated the HVR-B part from whole M protein-expressing bacteria. These data support a coherent model, in which the entire variable HVR-B part evades antibody attack, not only by sequence variability but also by weak immunogenicity resulting from protease attack.
Highlights
The gram-p ositive bacterium Streptococcus pyogenes is a human-specific pathogen responsible for mild throat and skin infections and for life-threatening conditions resulting in ~500,000 deaths annually (Carapetis et al 2005)
We identified a correlation between sequence variability and weak immunogenicity for M protein regions
On the basis of these data, we propose that the entire variable hypervariable region (HVR)-B part evades Ab attack through sequence variability, and through weak immunogenicity resulting from protease attack
Summary
The gram-p ositive bacterium Streptococcus pyogenes (group A Streptococcus) is a human-specific pathogen responsible for mild throat and skin infections and for life-threatening conditions resulting in ~500,000 deaths annually (Carapetis et al 2005). The most studied virulence factor of this pathogen is the polymorphic and surface-localized M protein, a dimeric coiled-coil molecule that inhibits phagocytosis and contributes to virulence by other mechanisms (Fischetti 1989; Waldemarsson et al 2009) This fibrillar protein has an amino-terminal and wall-distal hypervariable region (HVR), which exhibits extreme sequence variability among strains but not within a strain, allowing the identification of ~200 M (or emm) types (Steer et al 2009). We previously presented evidence that the HVR of an M protein elicits a much weaker antibody response than the remaining part of the protein, the HVR is a key target for protective Abs (Lannergård et al 2011) This property may seem paradoxical, but should be advantageous to the bacterium, by allowing it to escape anti-H VR Abs by two mechanisms, which act at different stages of an infection. On the basis of these data, we propose that the entire variable HVR-B part evades Ab attack through sequence variability, and through weak immunogenicity resulting from protease attack
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