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

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Jonas Lannergård, Bodil M. Kristensen, Mattias C. U. Gustafsson, Jenny J. Persson, Anna Norrby-Teglund, Margaretha Stålhammar-Carlemalm, Carl Gunnar Lindahl

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.

Original languageEnglish
JournalMicrobiologyOpen
Volume4
Issue number5
Pages (from-to)774-789
Number of pages16
ISSN2045-8827
DOIs
Publication statusPublished - 15 Jul 2015

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