COMPARISON OF THE RELATIVE TOXICITIES OF SHIGA-LIKE TOXINS TYPE-I ANDTYPE-II FOR MICE

In earlier studies using a streptomycin-treated mouse model of infecti on caused by enterobemorrhagic Escherichia coli (EHEC), animals fed Sh iga-like toxin type II (SLT-II)-producing strains developed acute rena l cortical necrosis and died, while mice fed Shiga-like toxin type I ( SLT-I)-producing clones did not die (E. A. Wadolkowski, L. M. Sung, J. A. Burris, J. E. Samuel, and A. D. O'Brien, Infect. Immun. 58:3959-39 65, 1990). To examine the bases for the differences we noted between t he two toxins in the murine infection model, we injected mice with pur ified toxins and carried out histopathological examinations. Despite t he genetic and structural similarities between the two toxins, SLT-II had a 50% lethal dose (LD50) which was approximately 400 times lower t han that of SLT-I when injected intravenously or intraperitoneally int o mice. Histopathologic examination of toxin-injected mice revealed th at detectable damage was limited to renal cortical tubule epithelial c ells. Passive administration of anti-SLT-II antibodies protected mice from SLT-II-mediated kidney damage and death. Immunofluorescence stain ing of normal murine kidney sections incubated with purified SLT-I or SLT-II demonstrated that both toxins bound to cortical tubule and medu llary duct epithelial cells. Compared with SLT-I, SLT-II was more heat and pH stable, suggesting that SLT-II is a relatively more stable mac romolecule. Although both toxins bound to globotriaosylceramide, SLT-1 bound with a higher affinity in a solid-phase binding assay. Differen ces in enzymatic activity between the two toxins were not detected. Th ese data suggest that structural/functional differences between the tw o toxins, possibly involving holotoxin stability and/or receptor affin ity, may contribute to the differential LD50s in mice.