The complete genome sequence of a chronic atrophic gastritis Helicobacter pylori strain: evolution during disease progression

Abstract

Helicobacter pylori produces acute superficial gastritis in nearly all of its human hosts. However, a subset of individuals develops chronic atrophic gastritis (ChAG), a condition characterized in part by diminished numbers of acid-producing parietal cells and increased risk for development of gastric adenocarcinoma. Previously, we used a gnotobiotic transgenic mouse model with an engineered ablation of parietal cells to show that loss of parietal cells provides an opportunity for a H. pylori isolate from a patient with ChAG (HPAG1) to bind to, enter, and persist within gastric stem cells. This finding raises the question of how ChAG influences H. pylori genome evolution, physiology, and tumorigenesis. Here we describe the 1,596,366-bp HPAG1 genome. Custom HPAG1 Affymetrix GeneChips, representing 99.6% of its predicted ORFs, were used for whole-genome genotyping of additional H. pylori ChAG isolates obtained from Swedish patients enrolled in a case-control study of gastric cancer, as well as ChAG- and cancer-associated isolates from an individual who progressed from ChAG to gastric adenocarcinoma. The results reveal a shared gene signature among ChAG strains, as well as genes that may have been lost or gained during progression to adenocarcinoma. Whole-genome transcriptional profiling of HPAG1's response to acid during in vitro growth indicates that genes encoding components of metal uptake and utilization pathways, outer membrane proteins, and virulence factors are among those associated with H. pylori's adaptation to ChAG.

Fig. 1.

Acid-regulated genes in HPAG1. Selected transcripts, differentially expressed in mid-log phase cells after incubation at pH 5.0 versus pH 7.0 for 1 and/or 3 h, are shown. Three independent experiments were performed. Numbers at the bottom indicate standard deviations above (red) or below (green) the mean level of expression (black) of a gene.

Fig. 2.

HPAG1 GeneChip-based genotyping of H. pylori strains isolated from a single patient who progressed from ChAG to gastric adenocarcinoma. H. pylori isolates were obtained from the antrum (HPAG-KX1A1) and corpus (HPAG-KX1C1) of a patient with ChAG. HPCa-KX2A2 (antrum) and HPCa-KX2C1 (corpus) are isolates obtained from the same patient 4 years later, when ChAG had progressed to gastric adenocarcinoma. Blue and yellow indicate the presence and absence of a gene, respectively.