SHIGA TOXIN MODE OF ACTION IN E. COLI O157:H7 DISEASE

Tom G. Obrig

Department of Microbiology and Immunology, University of Rochester, Box 672, 601 Elmwood Avenue, Rochester, NY 14642

Received 12/2/97 Accepted 12/8/97

7. A ROLE FOR SHIGA TOXINS IN VASCULAR DISEASE

7.1 Evidence for Stxs' role in EHEC-associated vascular disease

Some evidence indicating a role for the Shiga toxins at the vascular level are: 1) the production of active Shiga toxin is required for S. dysenteriae 1 to cause bloody dysentery, but not for watery diarrhea, in monkeys (6). 2) Stx has been detected in serum of HUS patients (3,37). 3) When purified Stx is presented to animals i.v., it targets to the endothelium, producing hemorrhagic lesions (7,38). 4) an E. coli 0157:H7 isolate was obtained from a patient with hemorrhagic colitis (HC) and when presented to rabbits intragastrically caused symptoms characteristic of HC in humans (39). In this study, gastrointestinal bleeding abnormalities appeared only if the bacteria synthesized Stx. 5) the overwhelming evidence, first presented by Karmali and others, of the incidence of Stx-production by E. coli isolates and the occurrence of HC and HUS in humans (20). 6) the association of HUS with a Stx-producing Citrobacter freundii isolate (41). 7) many patients exposed to Stx-producing EHEC produce circulating anti-Stx antibodies, indicating the toxin entered the blood. 8) the correlation that individuals belonging to the P1 blood group are less likely to get EHEC-associated HC and HUS because Stx binds to these erythrocytes (42,43). 9) isolated glomerular endothelial cells of humans are capable of expressing Gb3 and are exquisitely sensitive to the Stxs (24,44). 10) Gb3 is expressed on glomerular endothelial cells of young children (45). 11) purified Stx induces cytokine production in isolated monocyte/macrophage (46). 12) Stx1 presented to mice causes a renal-specific induction of a TNF promoter-encoded gene (47). 13) Stx1 induces expression of endothelial adhesion molecules for neutrophil adherence in static endothelial cell cultures and under laminar flow conditions (48).

7.2 Additional bacterial factors in EHEC-associated vascular disease

It is unlikely that Shiga toxins are the only factors produced by EHEC that lead to vascular damage. For example, E. coli O157:H7 elaborates an hemolysin, the gene for which is encoded on the large (60 mDa) plasmid (49). This toxin is capable of lysing eukaryotic cells (50). However, it is not known to what extent this toxin contributes to the virulence of EHEC. Other factors may be encoded by EHEC, but these will soon be identified as part of the E. coli genome sequencing project which has been extended to include EHEC bacteria (51).