Fis, a DNA nucleoid-associated protein, is involved in Salmonella typhimurium SPI-1 invasion gene expression

The ability of Salmonella enterica serovar Typhimurium to cause disease dep ends upon the co-ordinated expression of many genes located around the Salm onella chromosome. Specific pathogenicity loci, termed Salmonella pathogeni city islands, have been shown to be crucial for the invasion and survival o f Salmonella within host cells. Salmonella pathogenicity island 1 (SPI-1) h arbours the genes required for the stimulation of Salmonella uptake across the intestinal epithelia of the infected host. Regulation of SPI-1 genes is complex, as invasion gene expression responds to a number of different sig nals, presumably signals similar to those found within the environment of t he intestinal tract. As a result of our continued studies of SPI-1 gene reg ulation, we have discovered that the nucleoid-binding protein Fis plays a p ivotal role in the expression of HilA and InvF, two activators of SPI-1 gen es. A S. typhimurium fis mutant demonstrates a two- to threefold reduction in hilA::Tn5lacZY and a 10-fold reduction in invF::Tn5lacZY expression, as well as a 50-fold decreased ability to invade HEp-2 tissue culture cells. T his decreased expression of hilA and invF resulted in an altered secreted i nvasion protein profile in the fis mutant. Furthermore, the virulence of a S. typhimurium fis mutant is attenuated 100-fold when administered orally, but has wild-type virulence when administered intraperitoneally. Expression of hilA::Tn5lacZY and invF::Tn5lacZY in the fis mutant could be restored b y introducing a plasmid containing the S. typhimurium fis gene or a plasmid containing hilD, a gene encoding an AraC-like regulator of Salmonella inva sion genes.