title: 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.
authors.affiliation: Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Jonas
authors.initials: J
authors.lastname: Lannergård
authors.affiliation: Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Bodil M
authors.initials: BM
authors.lastname: Kristensen
authors.affiliation: Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Mattias C U
authors.initials: MC
authors.lastname: Gustafsson
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Persson
authors.affiliation: Center for Infectious Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Norrby-Teglund
authors.affiliation: Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Margaretha
authors.initials: M
authors.lastname: Stålhammar-Carlemalm
authors.affiliation: Department of Laboratory Medicine, Lund University, Lund, Sweden.|Department of Veterinary Disease Biology, University of Copenhagen, Frederiksberg C, Denmark.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindahl
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000235:genetics* / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics* / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology*; D014644:Genetic Variation; D006801:Humans; D057131:Immune Evasion; D051379:Mice; D013290:Streptococcal Infections / Q000276:immunology; D013297:Streptococcus pyogenes / Q000235:genetics* / Q000276:immunology*
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; C014689:streptococcal M protein
keywords: Antibody escape; group A Streptococcus; immunodominance; immunogenicity; protease sensitivity; sequence divergence