Abstract
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 into >220 M types, as defined by the M protein hypervariable region (HVR), has been considered to limit its utility as a vaccine immunogen due to type-specificity in the antibody response. Surprisingly, a multi-HVR immunogen in clinical vaccine trials was seen to elicit M type cross-reactivity. The basis for this cross-reactivity is unknown but may be due in part to antibody recognition of a three-dimensional (3D) pattern conserved in many M protein HVRs that confers binding to human C4b-binding protein (C4BP). To test this hypothesis, we examined whether a single M protein immunogen carrying the 3D pattern would elicit cross-reactivity against other M types carrying the 3D pattern. We found that a 34-amino acid sequence of M2 protein bearing the 3D pattern retained full C4BP-binding capacity when fused to a coiled coil-stabilizing sequence from GCN4. 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. The M2G antiserum recognized M proteins as 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, targeting the 3D pattern may prove advantageous in vaccine design.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
New experiments shown in figures 5, S6, S7, and S8.