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Comparison of Tissue-Selective Proinflammatory Gene Induction in Mice Infected with Wild-Type, DNA Adenine Methylase-Deficient, and Flagellin-Deficient Salmonella enterica ^,

Department of Molecular, Cellular and Developmental Biology, University of California at Santa Barbara, Santa Barbara, California 93106

Received 25 July 2007/ Accepted 7 September 2007

Mutants of Salmonella enterica serovar Typhimurium deficient in DNA adenine methylase (Dam) are attenuated for virulence in mice and confer heightened immunity in vaccinated animals. In contrast, infection of mice with wild-type (WT) strains or flagellin-deficient mutants of Salmonella causes typhoid fever. Here we examined the bacterial load and spatiotemporal kinetics of expression of several classes of host genes in Peyer's patches, the liver, and the spleen following oral infection of mice with WT, dam mutant, or flagellin-deficient (flhC) Salmonella. The genes evaluated included inflammatory (interleukin-1ß [IL-1ß], tumor necrosis factor alpha), chemokine (macrophage inflammatory protein 2), Th1/Th2 indicator (IL-12p40, IL-4), and interferon system (beta interferon [IFN-ß], IFN-, protein Mx1 GTPase, RNA-dependent protein kinase, inducible nitric oxide synthase, suppressor of cytokine signaling 1) beacons. We showed that maximal interferon system and proinflammatory gene induction occurred by 5 days after infection and that the levels were comparable for the WT and flhC strains but were significantly lower for the dam mutant. Additionally, host gene expression in systemic tissues of individual animals was dependent on the bacterial load in the Peyer's patches for mice infected with WT, dam mutant, or flhC mutant Salmonella as early as 8 h after infection. Moreover, a bacterial load threshold in the Peyer's patches was necessary to stimulate the host gene induction in the liver and spleen. Taken together, these results suggest that bacterial load and the accompanying strain-specific cytokine signature are important determinants of the host innate immune response and associated disease manifestations observed in dam mutant Salmonella-infected animals compared to the immune response and disease manifestations observed in WT and flhC mutant Salmonella-infected animals.

Published ahead of print on 24 September 2007.

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Editor: J. B. Bliska