Abstract
ABSTRACTInfection with Helicobacter pylori is a major risk factor for development of gastric disease, including gastric cancer. Patients infected with H. pylori strains that express CagA are at even greater risk of gastric carcinoma. Given the importance of CagA, this report describes a new molecular mechanism by which the cagA copy number dynamically expands and contracts in H. pylori. Analysis of strain PMSS1 revealed a heterogeneous population in terms of numbers of cagA copies; strains carried from zero to four copies of cagA that were arranged as direct repeats within the chromosome. Each of the multiple copies of cagA was expressed and encoded functional CagA; strains with more cagA repeats exhibited higher levels of CagA expression and increased levels of delivery and phosphorylation of CagA within host cells. This concomitantly resulted in more virulent phenotypes as measured by cell elongation and interleukin-8 (IL-8) induction. Sequence analysis of the repeat region revealed three cagA homologous areas (CHAs) within the cagA repeats. Of these, CHA-ud flanked each of the cagA copies and is likely important for the dynamic variation of cagA copy numbers. Analysis of a large panel of clinical isolates showed that 7.5% of H. pylori strains isolated in the United States harbored multiple cagA repeats, while none of the tested Korean isolates carried more than one copy of cagA. Finally, H. pylori strains carrying multiple cagA copies were differentially associated with gastric disease. Thus, the dynamic expansion and contraction of cagA copy numbers may serve as a novel mechanism by which H. pylori modulates gastric disease development.
Highlights
Infection with Helicobacter pylori is a major risk factor for development of gastric disease, including gastric cancer
The PMSS1 strain of H. pylori is capable of persistently colonizing mice and is a useful strain for the study of H. pylori infection in this animal model [52]
Our attempts to construct a PMSS1 derivative containing a clean deletion of cagA were repeatedly unsuccessful; PCR analysis of transformants yielded unexpected banding patterns that led us to postulate that PMSS1 may contain two tandem cagA genes, an observation that has not been made in any other strain of H. pylori
Summary
Infection with Helicobacter pylori is a major risk factor for development of gastric disease, including gastric cancer. In addition to toxin amino acid variation, the cagA promoter region has been shown to be genetically heterogeneous; an AATAAGATA motif located ϩ59 bp upstream of the transcription start site is associated with higher levels of CagA expression in H. pylori isolates from Colombia [26, 27] and Portugal [28]. These increased levels of CagA result in higher levels of interleukin-8 (IL-8) secretion by gastric cells in vitro. The amount of CagA expressed by H. pylori appears to be linked to downstream pathogenesis
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