title: The Hypervariable region of Streptococcus pyogenes M protein escapes antibody attack by antigenic variation and weak immunogenicity.
abstract: Sequence variation of antigenic proteins allows pathogens to evade antibody attack. The variable protein commonly includes a hypervariable region (HVR), which represents a key target for antibodies and is therefore predicted to be immunodominant. To understand the mechanism(s) of antibody evasion, we analyzed the clinically important HVR-containing M proteins of the human pathogen Streptococcus pyogenes. Antibodies elicited by M proteins were directed almost exclusively against the C-terminal part and not against the N-terminal HVR. Similar results were obtained for mice and humans with invasive S. pyogenes infection. Nevertheless, only anti-HVR antibodies protected efficiently against infection, as shown by passive immunizations. The HVR fused to an unrelated protein elicited no antibodies, implying that it is inherently weakly immunogenic. These data indicate that the M protein HVR evades antibody attack not only through antigenic variation but also by weak immunogenicity, a paradoxical observation that may apply to other HVR-containing proteins.
authors.affiliation: Division of Medical Microbiology, Department of Laboratory Medicine, Lund University, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Lannergård
authors.forename: Mattias C U
authors.initials: MC
authors.lastname: Gustafsson
authors.forename: Johan
authors.initials: J
authors.lastname: Waldemarsson
authors.forename: Anna
authors.initials: A
authors.lastname: Norrby-Teglund
authors.forename: Margaretha
authors.initials: M
authors.lastname: Stålhammar-Carlemalm
authors.forename: Gunnar
authors.initials: G
authors.lastname: Lindahl
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation; D000940:Antigenic Variation; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D001425:Bacterial Outer Membrane Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D002352:Carrier Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D007106:Immune Sera / Q000008:administration & dosage / Q000276:immunology; D007116:Immunization, Passive; D007117:Immunization, Secondary; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010587:Phagocytosis; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012698:Serologic Tests / Q000379:methods; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology; D013297:Streptococcus pyogenes / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D014611:Vaccination
chemical_list: D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002352:Carrier Proteins; D007106:Immune Sera; D011993:Recombinant Fusion Proteins; C014689:streptococcal M protein