Nickel-responsive induction of urease expression in Helicobacter pylori ismediated at the transcriptional level

The nickel-containing enzyme urease is an essential colonization factor of the gastric pathogen Helicobacter pylori, as it allows the bacterium to sur vive the acidic conditions in the gastric mucosa. Although urease can repre sents up to 10% of the total protein content of H. pylori, expression of ur ease genes is thought to be constitutive. Here it is demonstrated that H. p ylori regulates the expression and activity of its urease enzyme as a funct ion of the availability of the cofactor nickel. Supplementation of brucella growth medium with 1 or 100 muM NiCl2 resulted in up to 3.5-fold-increased expression of the urease subunit proteins UreA and UreB and up to 12-fold- increased urease enzyme activity. The induction was specific for nickel, si nce the addition of cadmium, cobalt, copper, iron, manganese, or zinc did n ot affect the expression of urease. Both Northern hybridization studies and a transcriptional ureA::lacZ fusion demonstrated that the observed nickel- responsive regulation of urease is mediated at the transcriptional level. M utation of the HP1027 gene, encoding the ferric uptake regulator (Fur), did not affect the expression of urease in unsupplemented medium but reduced t he nickel induction of urease expression to only twofold. This indicates th at Fur is involved in the modulation of urease expression in response to ni ckel. These data demonstrate nickel-responsive regulation of H. pylori urea se, a phenomenon likely to be of importance during the colonization and per sistence of H. pylori in the gastric mucosa.