The full expression of the Ity phenotype in Ity(r) mice requires C3 activation by Salmonella lipopolysaccharide

Our previous study has shown that the rapid and sufficient activation of co mplement by Salmonella lipopolysaccharide occurs in genetically resistant ( Ity(r)) A/J mice. To assess whether the level of complement activation by a virulent strain of Salmonella typhimurium regulates the level of murine na tural resistance, we compared levels of serum complement activation by S. t yphimurium and kinetics of serum-opsonized S. typhimurium grown in macropha ges using several strains of resistant (Ity(r)) and susceptible (Ity(s)) mi ce. Ity(s) macrophages killed intracellular S. typhimurium to the same exte nt as did Ity(r) macrophages when the pathogen was opsonized with Ity(r) se rum. Opsonization of S. typhimurium with Ity(s) serum reduced intracellular killing activity in Ity(r) macrophages to the same level as seen with Ity( s) macrophages. Incubation of S. typhimurium with 25% Mg2+ EGTA (5 mM MgCl2 -3 mM ethylene glycol-bis (beta-aminotheyl either)-N,N,N',N'-tetraacetic ac id)-chelated Ity(r) serum resulted in higher levels of C3 deposition onto t he surface of this bacteria, C3b generation and also C3 consumption, compar ed with that with Mg2+ EGTA-chelated Ity(s) serum. Opsonization of S. typhi murium with A/J serum prior to infection increased early resistance in Ity( s) mice. Infection with a virulent strain of S. typhimurium induced the exp ression of interleukin-10 (IL-10) mRNA at higher levels in C57BL/6 mice tha n in A/J mice. However, opsonization of S. typhimurium with A/J serum decre ased bacterial growth in the spleen of C57BL/6 mice to the same level as ob served for A/J mice in association with decreased expression levels of IL-I O mRNA. Moreover, administration of anti-C3 antibodies reduced the resistan ce of A/J mice in association with a decrease in serum levels of C3. These results indicate that the high level of complement activation via the alter native pathway in Ity(r) serum by a virulent strain of S. typhimurium reduc es the virulence of this pathogen, which may contribute to the full express ion of Ity phenotype in Ity(r) mice.