Fis is a key DNA-binding protein involved in nucleoid organization and modulation of many DNA transactions, including transcription in enteric bacteria. The regulon of genes whose expression is influenced by Fis in Salmonella enterica serovar Typhimurium (S. typhimurium) has been defined by DNA microarray analysis. These data suggest that Fis plays a central role in coordinating the expression of both metabolic and type III secretion factors. The genes that were most strongly up-regulated by Fis were those involved in virulence and located in the pathogenicity islands SPI-1, SPI-2, SPI-3 and SPI-5. Similarly, motility and flagellar genes required Fis for full expression. This was shown to be a direct effect as purified Fis protein bound to the promoter regions of representative flagella and SPI-2 genes. Genes contributing to aspects of metabolism known to assist the bacterium during survival in the mammalian gut were also Fis-regulated, usually negatively. This category included components of metabolic pathways for propanediol utilization, biotin synthesis, vitamin B 12 transport, fatty acids and acetate metabolism, as well as genes for the glyoxylate bypass of the tricarboxylic acid cycle. Genes found to be positively regulated by Fis included those for ethanolamine utilization. The data reported reveal the central role played by Fis in coordinating the expression of both housekeeping and virulence factors required by S. typhimurium during life in the gut lumen or during systemic infection of host cells.
INTRODUCTIONSalmonella enterica serovar Typhimurium (S. typhimurium) is the most common and best studied of the S. enterica serovars that infect humans (Finlay & Brumell, 2000). It is able to infect a range of animal species, including chicken, cattle and mice, and intensive study of this organism is providing important insights into key processes involved in bacterial pathogenesis. In the mouse, S. typhimurium is a facultative intracellular pathogen capable of invading epithelial cells and it has the ability to survive and proliferate within macrophages. The bacterium can be manipulated genetically with relative ease and the complete genome sequence is available (McClelland et al., 2001), allowing a combination of genetic analysis, cell biology and animal infection studies. This multidisciplinary approach has provided a picture of the major events involved when S. typhimurium infects the murine host. Following ingestion and passage through the stomach, the bacteria cross the lining of the intestine by invading the intestinal epithelium, predominantly via M cells. The Salmonellae are subsequently phagocytosed by macrophages before entering the blood stream and establishing a systemic infection (Finlay & Brumell, 2000; Galán, 2001;Groisman & Mouslim, 2000;Holden, 2002;Scherer & Miller, 2001).S. typhimurium is dependent upon the products of a large number of genes (up to 200) to cause infection (Finlay & Brumell, 2000). Some of the virulence genes are located on a 90 kb pathogenicity plasmid, of which the spv gen...