Sequence variability is correlated with weak immunogenicity in Streptococcus pyogenes M protein

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.

Structural determination ofStreptococcus pyogenesM1 protein interactions with human immunoglobulin G using integrative structural biology

“…Fibrinogen is an abundant plasma protein known to bind to the B-repeats of the M proteins [14,15]. Our results suggest that fibrinogen can mask the IgG epitopes in this region or that very few IgG binds to this region, as indicated in previously published work [35].…”

Serological responses of Australian horses using a commercial duplex indirect ELISA following vaccination against strangles

“…14,15 It is possible that the antibody response may have been primarily directed to other components of the SeM molecule, not the mpep1 fragment represented in the test antigen. 22 Our findings, however, confirm that the S. equi acidextracted vaccine Equivac®S/2in1 may elicit at least some antibody response to SeM. Minimal antibody responses were detected to AgA, representing the other cell wall-associated antigen SEQ2190, in stark contrast to previous reports in infected horses.…”

“…A stronger response to AgC may have been expected because it represents the highly antigenic cell wall‐associated SeM that is exposed during the extraction process . It is possible that the antibody response may have been primarily directed to other components of the SeM molecule, not the mpep1 fragment represented in the test antigen . Our findings, however, confirm that the S. equi acid‐extracted vaccine Equivac®S/2in1 may elicit at least some antibody response to SeM.…”

Variable region in streptococcal M-proteins provides stable binding with host fibrinogen for plasminogen-mediated bacterial invasion

“…that the high sequence variability within B-repeats may be due to immunogenic pressure (42). Our data demonstrate that, despite this pressure, their ability to bind to hFg is maintained.…”