A natural variant of the cysteine protease virulence factor of group A Streptococcus with an arginine-glycine-aspartic acid (RGD) motif preferentially binds human integrins alpha(v)beta(3) and alpha(IIb)beta(3)

The human pathogenic bacterium group A Streptococcus produces an extracellu lar cysteine protease [streptococcal pyrogenic exotoxin B (SpeB)] that is a critical virulence factor for invasive disease episodes. Sequence analysis of the speB gene from 200 group A Streptococcus isolates collected worldwi de identified three main mature SpeB (mSpeB) variants. One of these variant s (mSpeB2) contains an Arg-Gly-Asp (RGD) sequence, a tripeptide motif that is commonly recognized by integrin receptors. mSpeB2 is made by all isolate s of the unusually virulent serotype M1 and several other geographically wi despread clones that frequently cause invasive infections. Only the mSpeB2 variant bound to transfected cells expressing integrin alpha(v)beta(3) (als o known as the vitronectin receptor) or alpha(IIb)beta(3) (platelet glycopr otein IIb-IIIa), and binding was blocked by a mAb that recognizes the strep tococcal protease RGD motif region, In addition, mSpeB2 bound purified plat elet integrin alpha(IIb)beta(3). Defined beta(3) mutants that are altered f or fibrinogen binding were defective for SpeB binding, Synthetic peptides w ith the mSpeB2 RGD motif, but not the RSD sequence present in other mSpeB v ariants, blocked binding of mSpeB2 to transfected cells expressing alpha(v) beta(3) and caused detachment of cultured human umbilical vein endothelial cells, The results (i) identify a Gram-positive virulence factor that direc tly binds integrins, (ii) identify naturally occurring variants of a docume nted Gram-positive virulence factor with biomedically relevant differences in their interactions with host cells, and (iii) add to the theme that subt le natural variation in microbial virulence factor structure alters the cha racter of host-pathogen interactions.