Parameters underlying successful protection with live attenuated mutants in experimental shigellosis

Because the use of live attenuated mutants of Shigella spp, represents a pr omising approach to protection against bacillary dysentery (M. E. Etherridg e, A. T, M, Shamsul Hoque, and D, A. Sack, Lab. Anim, Sci, 46: 61-66, 1996) , it becomes essential to rationalize this approach in animal models in ord er to optimize attenuation of virulence in the vaccine candidates, as well as their route and mode of administration, and to define the correlates of protection. In this study, we have compared three strains of Shigella flexn eri 5-the wild-type M90T, an aroC mutant, and a double purE aroC mutant-for their pathogenicity, immunogenicity, and protective capacity. Protection a gainst keratoconjunctivitis, induced by wild-type M90T, was used as the pro tection read out in guinea pigs that were inoculated either intranasally or intragastrically, Following intranasal immunization, the aroC mutant elici ted weak nasal tissue destruction compared to M90T and achieved protection correlated with high levels of local anti-lipopolysaccharide immunoglobulin A (IgA), whereas the purE aroC double mutant, which also elicited weak tis sue destruction, was not protective and elicited a low IgA response, Conver sely, following intragastric immunization, only the M90T purE aroC double m utant elicited protection compared to both the aroC mutant and the wild-typ e strain. This mutant caused mild inflammatory destruction, particularly at the level of Peyer's patches, but it persisted much longer within the tiss ues. This could represent an essential parameter of the protective response that, in this case, did not clearly correlate with high anti-lipopolysacch aride IgA titers.