Hha Is a Negative Modulator of Transcription ofhilA, theSalmonella entericaSerovar Typhimurium Invasion Gene Transcriptional Activator

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Abstract
An early step in the establishment of Salmonella enterica serovar Typhimurium murine infection is the penetration of the intestinal mucosa of the small intestine. The majority of the genes responsible for the Salmonellainvasive phenotype are encoded on Salmonellapathogenicity island 1, and their transcription is controlled by thehilA transcriptional activator. The expression ofhilA is regulated by environmental signals including oxygen, osmolarity, pH, and growth phase such that the presence of any one suboptimal condition results in repression of hilAexpression and the invasive phenotype. We have conducted a search for negative regulators of hilA by introduction of aSalmonella enterica serovar Typhimurium chromosomal DNA gene bank into a Salmonella enterica serovar TyphimuriumhilA::Tn5lacZY reporter strain. This screen has identified the hha gene as a regulator that exerts a negative influence on hilA expression. Plasmid-encoded hha significantly reduceshilA::Tn5lacZY chromosomal expression, as well as expression of the invasion genesinvF, prgH, and sipC. Anhha null mutation results in substantial derepression of both chromosomally encoded and plasmid-encodedhilA::Tn5lacZY expression. Introduction of plasmid-encoded hha into strain SL1344 results in attenuation of invasion using in vitro and in vivo assays. Importantly, purified Hha protein was found to bind to ahilA DNA promoter fragment, suggesting that the regulatory activity of the Hha protein occurs at thehilA promoter. These data add detail to the developing model of the regulation of Salmonella invasion genes.