1887

Abstract

Activation of macrophages by interferon gamma (IFN-) and the subsequent production of nitric oxide (NO) are critical for the host defence against serovar Typhimurium infection. We report here the inhibition of IFN--induced NO production in RAW264.7 macrophages infected with wild-type . This phenomenon was shown to be dependent on the gene, which encodes a potential nitrite transporter. We observed a higher NO output from IFN--treated macrophages infected with a mutant of . The mutant also showed significantly decreased intracellular proliferation in a NO-dependent manner in activated RAW264.7 macrophages and in liver, spleen and secondary lymph nodes of mice, which was restored by complementing the gene . Under acidified nitrite stress, a twofold more pronounced NO-mediated repression of SPI2 was observed in the knockout strain compared to the wild-type. This enhanced SPI2 repression in the knockout led to a higher level of STAT-1 phosphorylation and inducible nitric oxide synthase (iNOS) expression than seen with the wild-type strain. In iNOS knockout mice, the organ load of the knockout strain was similar to that of the wild-type strain, indicating that the mutant is exclusively sensitive to the host nitrosative stress. Taken together, these results reveal that intracellular evade killing in activated macrophages by downregulating IFN--induced NO production, and they highlight the critical role of as a virulence gene.

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2009-08-01
2020-07-03
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