Immunity to Salmonella typhimurium infection in C3H/HeJ and C3H/HeNCrlBR mice: studies with an aromatic-dependent live S. typhimurium strain as a vaccine

Abstract

Immunization with avirulent Salmonella typhimurium strain SL3235, a smooth, aroA- derivative, was shown to induce high levels of resistance to challenge with virulent S. typhimurium in innately hypersusceptible C3H/HeJ mice and inherently resistant C3H/HeNCrlBR mice. Strain SL3235 is one of a class of avirulent aroA- derivatives made from various strains and species of Salmonella that are being considered as vaccine candidates for cattle and humans. This paper supports their efficacy and potential utility in this regard. In C3H/HeJ mice, immunity against over 1,000 50% lethal doses of virulent S. typhimurium was evident as early as 3 days after immunization and persisted for at least 7 months. Further, the vaccine was effective over a broad spectrum of doses, ranging from 10(4) to 10(6) organisms. Infection with SL3235 led to marked splenomegaly in both mouse strains. The relationship of splenomegaly to the growth kinetics and colonization by SL3235 in the spleens of infected C3H/HeJ and C3H/HeNCrlBR mice was followed. SL3235 initially multiplied slowly in the spleens of both mouse strains and then was rapidly cleared. Less multiplication was seen in the resistant C3H/HeNCrlBR mice than in C3H/HeJ mice. Maximum splenomegaly occurred after clearance of the organism had begun. Protection against virulent S. typhimurium persisted after virtually all of the SL3235 vaccine strain had been cleared from the spleen. Cross-protection against Listeria monocytogenes was evident, but had a later onset, waned by 21 days, and was not detectable by 1 month after vaccination. Demonstration of this cross-protection is consistent with the interpretation that SL3235 induces cellular immunity. One-week immune spleen cells adoptively transferred anti-S. typhimurium and anti-L. monocytogenes immunity. T cell-enriched fractions were ineffective in adoptive transfer, as were spleen cells taken 2 weeks or later after immunization. Protective capacity was in the adherent cell fraction and seemed to be associated with macrophages. Evidence for induction of a population of sensitized T cells was obtained by using a peritoneal exudate T-lymphocyte proliferation assay on peritoneal T lymphocytes collected 1 to 3 months after SL3235 infection.