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 intracellular pathogen of macrophages. In the present study we questioned the contribution that expression of substance P receptors makes to the protective response following oral inoculation with a lethal dose of Salmonella. Such a relationship was suggested when oral inoculation with Salmonella induced rapid and dramatic increases in substance P receptor mRNA expression within Peyer's patches and mesenteric lymph nodes and subsequently in the spleen. The importance of substance P receptor expression in vivo was further suggested by pretreatment of mice with the substance P antagonist, spantide II, before oral inoculation with Salmonella. Mice pretreated with spantide II and then orally inoculated developed advanced salmonellosis and had significantly reduced survival rates compared with mice pretreated with a control peptide. Treatment with spantide II significantly reduced early Salmonella-induced IL-12p4O and IFN-gamma mRNA expression at mucosal sites, suggesting a mechanism for the reduced ability of spantide II-treated mice to resist this pathogen. Increased susceptibility to salmonellosis was not due to 1) spantide II-induced alterations in the uptake of this pathogen from the gut, 2) global spantide II-mediated immune suppression, or 3) nonsubstance 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 against this intracellular pathogen might be a direct effect of substance P on this cell population.
Kincy-Cain
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Department of Microbiology and Immunology, Tulane University Medical Center, New Orleans, LA 70112, USA.
Bost
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KL
D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004198:Disease Susceptibility; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis / Q000235:genetics; D012481:Salmonella Infections, Animal / Q000209:etiology* / Q000276:immunology* / Q000401:mortality; D013373:Substance P / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology
D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; C065446:spantide II; D018664:Interleukin-12; D013373:Substance P; D007371:Interferon-gamma