is a neutralophilic, gram-negative, ureolytic organism that is able to colonize the human stomach but does not survive in a defined medium with a pH <4.0 unless urea is present. In order to live in the gastric environment, it has developed a repertoire of acid resistance mechanisms that can be classified into time-independent, acute, and chronic responses. Time-independent acid resistance depends on the structure of the organism's inner and outer membrane proteins that have a high isoelectric point, thereby reducing their proton permeability. Acute acid resistance depends on the constitutive synthesis of a neutral pH optimum urease that is an oligomeric Ni2+-containing heterodimer of UreA and UreB subunits. Gastric juice urea is able to rapidly access intrabacterial urease when the periplasmic pH falls below ∼6.2 owing to pH-gating of a urea channel, UreI. This results in the formation of NH, which then neutralizes the bacterial periplasm to provide a pH of ∼6.2 and an inner membrane potential of −101 mV, giving a proton motive force of ∼−200 mV. UreI is a six-transmembrane segment protein, with homology to the genes of the amidase gene cluster and to UreI of and . Expression of these UreI proteins in oocytes has shown that UreI of and can transport urea only at acidic pH, whereas that of is open at both neutral and acidic pH. Site-directed mutagenesis and chimeric analysis have identified amino acids implicated in maintaining the closed state of the channel at neutral pH and other amino acids that play a structural role in channel function. Deletion of abolishes the ability of the organism to survive in acid and also to colonize the mouse or gerbil stomach. However, if acid secretion is inhibited in gerbils, the deletion mutants do colonize but are eradicated when acid secretion is allowed to return, showing that UreI is essential for gastric survival and that the habitat of at the gastric surface must fall to pH 3.5 or below. The chronic response is from increased Ni2+ insertion into the apo-enzyme, which results in a threefold increase in urease, which is also dependent on expression of UreI. This allows the organism to live in either gastric fundus or gastric antrum depending on the level of acidity at the gastric surface. There are other effects of acid on transcript stability that may alter levels of protein synthesis in acid. Incubation of the organism at acidic pH also results in regulation of expression of a variety of genes, such as some outer membrane proteins, that constitutes an acid tolerance response. Understanding of these acid resistance and tolerance responses should provide novel eradication therapies for this carcinogenic gastric pathogen.


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  • Article Type: Review Article
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