@article{mbs:/content/journal/micro/10.1099/mic.0.029611-0, author = "Das, Priyanka and Lahiri, Amit and Lahiri, Ayan and Chakravortty, Dipshikha", title = "Novel role of the nitrite transporter NirC in Salmonella pathogenesis: SPI2-dependent suppression of inducible nitric oxide synthase in activated macrophages", journal= "Microbiology", year = "2009", volume = "155", number = "8", pages = "2476-2489", doi = "https://doi.org/10.1099/mic.0.029611-0", url = "https://www.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.029611-0", publisher = "Microbiology Society", issn = "1465-2080", type = "Journal Article", keywords = "FBS, fetal bovine serum", keywords = "NED, N-(naphthyl)ethylenediamine dihydrochloride", keywords = "SPI2, Salmonella pathogenicity island 2", keywords = "MLN, mesenteric lymph nodes", keywords = "iNOS, inducible nitric oxide synthase", keywords = "IFN-γ, interferon gamma", keywords = "ROI, reactive oxygen intermediates", keywords = "L-NIL, l-N6-iminoethyllysine", keywords = "BMDM, bone-marrow-derived macrophages", keywords = "SOCS-3, suppressor of cytokine signalling-3", keywords = "RNS, reactive nitrogen species", keywords = "JAK-STAT, Janus kinase/signal transducer and activator of transcription", abstract = "Activation of macrophages by interferon gamma (IFN-γ) and the subsequent production of nitric oxide (NO) are critical for the host defence against Salmonella enterica serovar Typhimurium infection. We report here the inhibition of IFN-γ-induced NO production in RAW264.7 macrophages infected with wild-type Salmonella. This phenomenon was shown to be dependent on the nirC gene, which encodes a potential nitrite transporter. We observed a higher NO output from IFN-γ-treated macrophages infected with a nirC mutant of Salmonella. The nirC 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 in trans. Under acidified nitrite stress, a twofold more pronounced NO-mediated repression of SPI2 was observed in the nirC knockout strain compared to the wild-type. This enhanced SPI2 repression in the nirC 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 nirC 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 Salmonella evade killing in activated macrophages by downregulating IFN-γ-induced NO production, and they highlight the critical role of nirC as a virulence gene.", }