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J. Bacteriol. doi:10.1128/JB.00726-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

FNR is a Global Regulator of Virulence and Anaerobic Metabolism in Salmonella enterica serovar Typhimurium (ATCC 14028s)

Department of Microbiology, North Carolina State University, Raleigh, NC 27695-7615; Sidney Kimmel Cancer Center, San Diego, CA 92121; Department of Microbiology, University of Colorado Health Sciences Center, Denver, CO 80262; Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195-7110

^* To whom correspondence should be addressed. Email: hosni_hassan{at}ncsu.edu.

	Abstract

Salmonella enterica serovar Typhimurium must successfully transition the broad fluctuations in [oxygen] encountered in the host. In Escherichia coli, FNR is one of the main regulatory proteins involved in O₂ - sensing. To assess the role of FNR in S. Typhimurium, we constructed an isogenic fnr mutant in the virulent wild-type strain (ATCC 14028s) and compared their transcriptional profiles and pathogenicity in mice. Here, we report that, under anaerobic conditions, 311 genes (6.80% of the genome) are regulated directly or indirectly by FNR; of these, 87 genes (28%) are poorly characterized. Regulation by FNR in S. Typhimurium is similar, but distinct from that in E. coli. Thus, genes/operons involved in aerobic metabolism, NO^.-detoxification, flagellar biosynthesis, motility, chemotaxis, and anaerobic carbon utilization are regulated by FNR in a similar fashion as in E. coli. However, genes/operons existing in E. coli, but regulated by FNR only in S. Typhimurium include those coding for ethanolamine utilization, a universal stress protein, a ferritin-like protein, and a phosphotransacetylase. Interestingly, Salmonella-specific genes/operons regulated by FNR include numerous virulence genes within Salmonella pathogenicity island 1 (SPI-1), newly identified flagellar genes (mcpAC, cheV), and the virulence operon (srfABC). Furthermore, the role of FNR as a positive regulator of motility, flagella biosynthesis, and pathogenesis was confirmed by showing that the mutant is non-motile, lacks flagella, is attenuated in mice, and does not survive inside macrophages. The inability of the mutant to survive inside macrophages is likely due to its sensitivity to the reactive oxygen species generated by NADPH phagocyte oxidase.

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