Representative Shigella flexneri strains were studied to determine whether plasmids are involved in their virulence. All invasive S. flexneri strains, irrespective of serotype, were found to harbor a large plasmid of approximately 140 megadaltons in size, although some strains carried additional plasmid species. Spontaneous variants of strains of serotypes 1, 2, and 5 had lost this 140-megadalton plasmid and had concomitantly become avirulent, i.e., could neither invade HeLa cell monolayers nor produced keratoconjunctivitis in guinea pigs. To monitor plasmid transfer, the 140-megadalton plasmid of strain M90T (serotype 5) was tagged with the kanamycin resistance transposon Tn5. This tagged plasmid, pWR110, was not self-transmissible, but was mobilized by one of several different conjugative plasmids into avirulent derivatives of the heterologous serotypes 1 and 2 which had lost the comparable large plasmid. Transconjugants of both serotypes which had received pWR110 regained virulence. These data directly demonstrate that this large S. flexneri plasmid encodes or regulates some function(s) required for epithelial cell penetration.

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Epithelial cell penetration as an essential step in the pathogenesis of bacillary dysentery. J. Bacteriol. 88:1503-1518. 1964.-A parent strain of Shigella flexneri 2a and a colonial mutant derived from it were studied in three animal models. Both strains were equally virulent for mice when living cells suspended in hog gastric mucin were injected by the intraperitoneal route. Feeding the parent strain to starved guinea pigs, followed by the intraperitoneal injection of opium, resulted in the formation of ulcerative lesions in the intestinal tract and in the death of these animals. When the colonial variant was fed to similarly prepared

Strains of Escherichia coli previously implicated or proven to be causes of diarrhea were examined for production of a toxin similar to that of Shigella dysenteriae type 1 (Shiga). Organisms grown in an iron-depleted broth were lysed by pressure disruption followed by ultracentrifugation. Saline-dialyzed extracts were tested for cytotoxic effects on HeLa cells that were neutralizable with antiserum to Shiga toxin. Among the 13 E. coli strains so analyzed, 11 made a Shiga-like cytotoxin in levels ranging from trace (two avirulent isolates) to amounts equivalent to S. dysenteriae type 1 (two noninvasive strains that did not make E. coli heat-labile or -stable enterotoxins but were isolated from infants with diarrhea). As with extracts of Shiga toxin, lysates of these E. coli strains that produced high levels of Shiga-like toxin were enterotoxic for rabbits, paralytic and lethal for mice, and inhibited protein synthesis in HeLa cells. Thus, these data suggest that Shiga-like toxin may be another heretofore undiscovered factor in the pathogenesis of diarrhea caused by some E. coli strains.

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