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 αvβ3 and «nbßj

Kathryn E. Stockbauer, Loranne Magoun, Mengyao Liu, Eugene H. Burns, Siddeswar Gubba, Sarah Renish, Xi Pan, Sarah C. Bodary, Elizabeth Baker, Jenifer Coburn, John M. Leong, James M. Musser

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

The human pathogenic bacterium group A Streptococcus produces an extracellular 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 worldwide identified three main mature SpeB (mSpeB) variants. One of these variants (mSpeB2) contains an Arg-Gly-Asp (RGD) sequence, a tripeptide motif that is commonly recognized by integrin receptors, mSpeB2 is made by all isolates of the unusually virulent serotype M1 and several other geographically widespread clones that frequently cause invasive infections. Only the mSpeB2 variant bound to transfected cells expressing integrin α(v)β3 (also known as the vitronectin receptor) or α(IIb)β3 (platelet glycoprotein IIb-IIIa), and binding was blocked by a mAb that recognizes the streptococcal protease RGD motif region. In addition, mSpeB2 bound purified platelet integrin α(IIb)β3. Defined β3 mutants that are altered for fibrinogen binding were defective for SpeB binding. Synthetic peptides with the mSpeB2 RGD motif, but not the RSD sequence present in other mSpeB variants, blocked binding of mSpeB2 to transfected cells expressing α(v)β3 and caused detachment of cultured human umbilical vein endothelial cells. The results (i) identify a Gram-positive virulence factor that directly binds integrins, (ii) identify naturally occurring variants of a documented Gram- positive virulence factor with biomedically relevant differences in their interactions with host cells, and (iii) add to the theme that subtle natural variation in microbial virulence factor structure alters the character of host-pathogen interactions.

Original languageEnglish (US)
Pages (from-to)242-247
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number1
DOIs
StatePublished - Jan 5 1999

ASJC Scopus subject areas

  • General

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