The horizontal transfer of virulence genes between bacteria raises the question of how expression of these genes is regulated in ways that will benefit their new host. The heat-stable nucleoid-structuring (H-NS) protein acts as a sentinel to silence foreign gene expression by binding to intrinsically curved DNA sequences which occur at bacterial gene promoters. This allows the new genes to be incorporated into the genome without causing a competitive disadvantage. However, if bacteria are to benefit from newly-acquired virulence genes, they need to be temporally and spatially expressed. This can be achieved by transcriptional activators, such as those of the AraC family, which anatgonise and relieve H-NS repression.
Enteropathogenic E. coli (EPEC) is a leading cause of diarrhoea in children. The major virulence determinant of EPEC is a horizontally-acquired ~35-kb pathogenicity island, known as the locus of enterocyte effacement (LEE), which encodes a type III secretion system and effector proteins that are required for virulence. Bioinformatic analysis of a rabbit-specific EPEC strain, E22, revealed two AraC-like regulators, RegR and RalR. RegR is a global virulence regulator of strain E22 that responds to the gut-associated signal, bicarbonate, to activate transcription of its regulon which includes the genes for three different adhesins. The RalR regulator, whose expression is also activated by RegR, controls the expression of several other virulence determinants, including an adhesin known as Ral. Knocking out either regR or ralR severely attenuates the ability of E22 to colonise rabbits, confirming that virulence factors other than the LEE are required for full virulence of this EPEC strain. We are currently targeting virulence regulators and their associated regulons to identify markers that can be used in PCR-based diagnostic assays to detect virulent subsets of EPEC. In addition, advancing our understanding of the mechanisms of virulence regulation may assist the development of novel strategies to combat bacterial pathogens.