The Journal of Experimental Medicine
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Published online 28 June 2004 doi:10.1084/jem.20040392
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 1, 35-46
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A New Family of Potent AB5 Cytotoxins Produced by Shiga Toxigenic Escherichia coli

Adrienne W. Paton, Potjanee Srimanote, Ursula M. Talbot, Hui Wang, and James C. Paton

School of Molecular and Biomedical Science, University of Adelaide, South Australia, 5005, Australia

Address correspondence to James C. Paton, School of Molecular and Biomedical Science, University of Adelaide, South Australia, 5005, Australia. Phone: 61-8-83035929; Fax: 61-8-83033262; email: james.paton{at}adelaide.edu.au

The Shiga toxigenic Escherichia coli (STEC) O113:H21 strain 98NK2, which was responsible for an outbreak of hemolytic uremic syndrome, secretes a highly potent and lethal subtilase cytotoxin that is unrelated to any bacterial toxin described to date. It is the prototype of a new family of AB5 toxins, comprising a single 35-kilodalton (kD) A subunit and a pentamer of 13-kD B subunits. The A subunit is a subtilase-like serine protease distantly related to the BA_2875 gene product of Bacillus anthracis. The B subunit is related to a putative exported protein from Yersinia pestis, and binds to a mimic of the ganglioside GM2. Subtilase cytotoxin is encoded by two closely linked, cotranscribed genes (subA and subB), which, in strain 98NK2, are located on a large, conjugative virulence plasmid. Homologues of the genes are present in 32 out of 68 other STEC strains tested. Intraperitoneal injection of purified subtilase cytotoxin was fatal for mice and resulted in extensive microvascular thrombosis, as well as necrosis in the brain, kidneys, and liver. Oral challenge of mice with E. coli K-12–expressing cloned subA and subB resulted in dramatic weight loss. These findings suggest that the toxin may contribute to the pathogenesis of human disease.

Key Words: subtilase • enterohemorrhagic E. coli • serine protease • hemolytic uremic syndrome • microvascular thrombosis

Abbreviations used in this paper: aa, amino acid; CHO, Chinese hamster ovary; HUS, hemolytic uremic syndrome; IPTG, isopropyl-ß-D-thiogalactopyranoside; LB, Luria-Bertani; nt, nucleotide; Ni-NTA, nickel nitrilotriacetic acid; ORF, open reading frame; Ptx, pertussis toxin; STEC, Shiga toxigenic Escherichia coli; Stx, Shiga toxin.


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