A conserved 3D pattern in a Streptococcus pyogenes M protein immunogen elicits M-type crossreactivity.
J Biol Chem
; 299(8): 104980, 2023 08.
Article
in En
| MEDLINE
| ID: mdl-37390991
Coiled coil-forming M proteins of the widespread and potentially deadly bacterial pathogen Streptococcus pyogenes (strep A) are immunodominant targets of opsonizing antibodies. However, antigenic sequence variability of M proteins into >220 M types, as defined by their hypervariable regions (HVRs), is considered to limit M proteins as vaccine immunogens because of type specificity in the antibody response. Surprisingly, a multi-HVR immunogen in clinical vaccine trials was shown to elicit M-type crossreactivity. The basis for this crossreactivity is unknown but may be due in part to antibody recognition of a 3D pattern conserved in many M protein HVRs that confers binding to human complement C4b-binding protein (C4BP). To test this hypothesis, we investigated whether a single M protein immunogen carrying the 3D pattern would elicit crossreactivity against other M types carrying the 3D pattern. We found that a 34-amino acid sequence of S. pyogenes M2 protein bearing the 3D pattern retained full C4BP-binding capacity when fused to a coiled coil-stabilizing sequence from the protein GCN4. We show that this immunogen, called M2G, elicited cross-reactive antibodies against a number of M types that carry the 3D pattern but not against those that lack the 3D pattern. We further show that the M2G antiserum-recognized M proteins displayed natively on the strep A surface and promoted the opsonophagocytic killing of strep A strains expressing these M proteins. As C4BP binding is a conserved virulence trait of strep A, we propose that targeting the 3D pattern may prove advantageous in vaccine design.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Streptococcus pyogenes
/
Bacterial Outer Membrane Proteins
/
Carrier Proteins
/
Antigens, Bacterial
Limits:
Humans
Language:
En
Journal:
J Biol Chem
Year:
2023
Document type:
Article
Affiliation country:
United States
Country of publication:
United States