IMMUNOSUPPRESSION AND NITRIC-OXIDE PRODUCTION INDUCED BY PARENTERAL LIVE SALMONELLA VACCINES DO NOT CORRELATE WITH PROTECTIVE CAPACITY - A PHOP--TN10 MUTANT DOES NOT SUPPRESS BUT DOES PROTECT

Previous work from our laboratory showed that an aroA mutant strain of S. typhimurium, SL3235, induces profound immunosuppression 7 days pos t-parenteral inoculation, and that the suppression is mediated by nitr ic oxide. Suppression was measured by the capacity of spleen cells to mount a primary in vitro plaque-forming cell response to sheep red blo od cells in Mishell-Dutton cultures. In the present studies, the capac ity of a panel of strains of attenuated Salmonella with various geneti c lesions was tested. Most of the strains were S. typhimurium, but sev eral were S. dublin It was found that a variety of Salmonella strains induced suppression, demonstrating that suppressive capacity is not un ique to SL3235 or to S. typhimurium. A strong correlation was obtained between the log(10) of the microbial burden (cfu spleen(-1)) on the s eventh day post-vaccine inoculation and the degree of immunosuppressio n. Strains that gave high spleen counts gave greater suppression. Micr obial burden also correlated with the size of the spleen and the amoun t of nitrite produced by spleen-cell cultures, a measure of nitric oxi de. Finally, the degree of immunosuppression was found to be linearly related to the log(10) of the amount of nitrate produced. The capacity of the various strains of Salmonella to protect against challenge wit h virulent S. typhimurium, strain W118-2, was also tested. No correlat ion was found between suppressive and protective capacities of the var ious strains. Two strains suppressed, but did not protect. While most strains that protected grew or persisted in vivo, a phoP::Tn10 mutant of S. typhimurium did not grow or persist; this phoP mutant did not ca use immunosuppression, but gave 100% protection against challenge with wild type S. typhimurium, suggesting that such mutants have advantage ous properties as live vaccines. (C) 1997 Elsevier Science Ltd.