The Slr protein of Streptococcus pyogenes is selectively expressed in vivo and is a target for protective antibodies.

Vaccine candidates are typically identified through characterization of microbial surface antigens expressed under laboratory conditions. Here, we studied the major human pathogen Streptococcus pyogenes and showed that Slr, a lipoprotein encoded by all strains, is not detected on the bacterial surface during growth in broth but nevertheless is targeted by protective antibodies in vivo, as demonstrated by passive and active immunizations in a mouse model of invasive infection. The expression of Slr is governed by the zinc-controlled regulator AdcR, indicating that zinc depletion triggers surface expression of Slr in vivo. During infection in humans and mice, the antibody response to Slr is comparable to that elicited by the classical M protein and is, intriguingly, directed almost exclusively against a region with histidine triad (HT) motifs, an outcome that may represent a mechanism of immune escape. For vaccine development, these data focus interest on Slr and other microbial surface proteins selectively expressed in vivo.