INCREASED SUSCEPTIBILITY OF MICE TO SALMONELLA INFECTION FOLLOWING IN-VIVO TREATMENT WITH THE SUBSTANCE-P ANTAGONIST, SPANTIDE-II

Successful resolution of salmonellosis in naive mice depends in large part upon IL-12-induced IFN-gamma production to eliminate this intrace llular pathogen of macrophages. In the present study we questioned the contribution that expression of substance P receptors makes to the pr otective response following oral inoculation with a lethal dose of Sal monella. Such a relationship was suggested when oral inoculation with Salmonella induced rapid and dramatic increases in substance P recepto r mRNA expression within Peyer's patches and mesenteric lymph nodes an d subsequently in the spleen. The importance of substance P receptor e xpression in vivo was further suggested by pretreatment of mice with t he substance P antagonist, spantide II, before oral inoculation with S almonella. Mice pretreated with spantide II and then orally inoculated developed advanced salmonellosis and had significantly reduced surviv al rates-compared with mice pretreated with a control peptide. Treatme nt with spantide II significantly reduced early Salmonella-induced IL- 12p40 and IFN-gamma mRNA expression at mucosal sites, suggesting a mec hanism for the reduced ability of spantide II-treated mice to resist t his pathogen. Increased susceptibility to salmonellosis was not due to 1) spantide II-induced alterations in the uptake of this pathogen fro m the gut, 2) global spantide Ii-mediated immune suppression, or 3) no nsubstance P receptor-mediated effects of spantide II on macrophages. The ability of Salmonella to induce substance P receptor expression on cultured macrophages suggested that one mechanism for resistance agai nst this intracellular pathogen might be a direct effect of substance P on this cell population.