Strains of Shigella flexneri with different invasive and pathogenic potentials were inoculated into the intestinal lumen of acutely ligated loops in nonimmune rabbits. After 90 min, tissues processed for ultrastructural as well as light microscopy showed that the bacilli were phagocytosed by M cells over lymphoid follicles of Peyer's patches and carried in vacuoles into the epithelium. Nonpathogenic as well as pathogenic strains were readily taken up regardless of the presence of the 140-megadalton virulence plasmid. More virulent than avirulent shigellae were found in M cells at 90 min, reflecting replication or preferential uptake of the virulent strains. Heat-killed shigellae of the virulent strain were taken up by M cells to the same degree as the avirulent strains. Incubation of the bacteria for 18 h resulted in surface ulceration which was limited to epithelium overlying lymphoid follicles (M cell areas) in acute loops exposed to the virulent shigellae. Villus epithelium adjacent to the ulcerated follicular domes was intact, although there was mucus depletion. In the present study, we found that pathogenic shigellae appear to replicate in the M cells, escape from the phagocytic vesicles, and thereby initiate the ulcerations in this experimental model of dysentery. While initial antigen processing in the gut for a mucosal immune response may require uptake of luminal microorganisms by M cells, this may pose a threat under some circumstances.
Although the role of Shiga toxin in dysentery is unknown, the toxin is cytotoxic to HeLa cells, causes fluid secretion in rabbit intestine, and is lethal to rabbits and mice when injected parenterally. In the present study, rabbits received three weekly doses of Shiga toxin directly into chronically isolated ileal loops. Within a week, secretions from these loops contained immunoglobulin A (IgA) anti-Shiga toxin. The titer of IgA anti-Shiga toxin increased after weekly doses 2 and 3. Little IgG anti-Shiga toxin was present in loop secretions, although high titers of IgG anti-Shiga toxin were found in the sera. These loop secretions were able to neutralize the cytotoxic effects of Shiga toxin in the HeLa cell assay. The capacity to neutralize the cytotoxicity of the toxin correlated strongly with the IgA anti-Shiga toxin titer in these same secretions. Pooled immune loop secretions were also able to significantly reduce fluid accumulation in acutely ligated loops in rabbits, while loop secretions from control rabbits could not. Shiga toxin elicited a strong secretory IgA response upon application to the intestine. Further, the mucosal antibodies produced functioned to prevent the toxic effects of Shiga toxin both in vitro and in vivo.
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