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

TY - JOUR

T1 - Sequence variability is correlated with weak immunogenicity in Streptococcus pyogenes M protein

AU - Lannergård, Jonas

AU - Kristensen, Bodil M.

AU - Gustafsson, Mattias C. U.

AU - Persson, Jenny J.

AU - Norrby-Teglund, Anna

AU - Stålhammar-Carlemalm, Margaretha

AU - Lindahl, Carl Gunnar

N1 - © 2015 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

PY - 2015/10

Y1 - 2015/10

N2 - 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.

AB - 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.

KW - Faculty of Health and Medical Sciences

KW - Antibody escape

KW - group A Streptococcus

KW - immunodominance

KW - immunogenicity

KW - protease sensitivity

KW - sequence divergence

U2 - 10.1002/mbo3.278

DO - 10.1002/mbo3.278

M3 - Journal article

C2 - 26175306

SN - 2045-8827

VL - 4

SP - 774

EP - 789

JO - MicrobiologyOpen

JF - MicrobiologyOpen

IS - 5

ER -