Gastric infection by Helicobacter pylori

Abstract

Helicobacter pylori infects half of the world's population and plays a causal role in ulcer disease and gastric cancer. This pathogenic neutralophile uniquely colonizes the acidic gastric milieu through the process of acid acclimation. Acid acclimation is the ability of the organism to maintain periplasmic pH near neutrality in an acidic environment to prevent a fall in cytoplasmic pH in order to maintain viability and growth in acid. Recently, due to an increase in antibiotic resistance, the rate of H. pylori eradication has fallen below 80% generating renewed interest in novel eradication regimens and targets. In this article, we review the gastric biology of H. pylori and acid acclimation, various detection procedures, antibiotic resistance and the role that gastric acidity plays in the susceptibility of the organism to antibiotics currently in use and propose several novel drug targets that would promote eradication in the absence of antibiotics.

Fig. 1

Periplasmic buffering and regulation by Helicobacter pylori. Urea crosses the outer membrane (OM) and then the inner membrane (IM) through the H⁺ gated urea channel, UreI, at external pH<6.0. Cytoplasmic urease hydrolyzes urea to 2NH₃ + H₂CO₃, and the latter is converted to CO₂ by cytoplasmic β-carbonic anhydrase (β-CA). These gases cross the IM and the CO₂ is converted to HCO₃⁻ by the membrane bound α-carbonic anhydrase (α-CA), thereby maintaining periplasmic pH at ~6.1, which is the effective pK_a (−log₁₀K_a, in which K_a is the acid dissociation constant) of the CO₂/HCO₃⁻ couple. Exiting NH₃ neutralizes the H⁺ that is produced by carbonic anhydrase as well as the entering H⁺, and can also exit the OM to alkalize the medium. This allows maintenance of a periplasmic pH that is much higher than the medium (left side) [12, 44, 45]. The role of the pH responsive two component system (TCS) FlgS (encoded by the locus HP0244) in acid acclimation by H. pylori (middle) Activation of this TCS results in recruitment of the urease proteins to UreI: the resultant immediate access of urea to urease and the outward transport of CO₂, NH₃ and NH₄⁺ through UreI increase the rates of periplasmic buffering and disposal of cytoplasmic NH₄+ [12, 13, 44, 45]. A simplified model representing regulation of the expression of the urease apoenzyme genes (ureA and ureB) by the ArsRS TCS (encoded by loci HP0166 (ArsR) and HP0165 (ArsS)). At neutral pH, ArsS is not activated and the response regulator, ArsR, is not phosphorylated. The unphosphorylated ArsR binds to the promoter of the gene encoding a small RNA (ureB-sRNA) that targets the ureB part of the ureAB mRNA, leading to transcription of ureB-sRNA and consqueny truncation of the ureAB mRNA, resulting in a decline in urease activity. This reflects the adaptation to non-acidic pH. At acidic pH, ArsS is activated and ArsR is phosphorylated; the phosphorylated ArsR binds to the ureAB promoter to positively regulated the transcription of ureAB, resulting in upregulation of the ureAB mRNA and a consequent increase in urease activity (right)

Fig. 2

Survival and antibiotic sensitivity of H. pylori at different medium pH in vitro in the absence of urea. H. pylori grows at a narrow external pH range between 6 and 7 and are sensitive to the growth dependent antibiotics such as amoxicillin, clarithromycin or tetracycline (yellow bars). Although, H. pylori is able to survive at external pHs between 4 and 6 (blue bars) there is little growth decreasing the efficacy of the growth dependent antibiotics (blue bars)