Identification of Helicobacter pylori Genes That Contribute to Stomach Colonization

Abstract

Chronic infection of the human stomach by Helicobacter pylori leads to a variety of pathological sequelae, including peptic ulcer and gastric cancer, resulting in significant human morbidity and mortality. Several genes have been implicated in disease related to H. pylori infection, including the vacuolating cytotoxin and the cag pathogenicity island. Other factors important for the establishment and maintenance of infection include urease enzyme production, motility, iron uptake, and stress response. We utilized a C57BL/6 mouse infection model to query a collection of 2,400 transposon mutants in two different bacterial strain backgrounds for H. pylori genetic loci contributing to colonization of the stomach. Microarray-based tracking of transposon mutants allowed us to monitor the behavior of transposon insertions in 758 different gene loci. Of the loci measured, 223 (29%) had a predicted colonization defect. These included previously described H. pylori virulence genes, genes implicated in virulence in other pathogenic bacteria, and 81 hypothetical proteins. We have retested 10 previously uncharacterized candidate colonization gene loci by making independent null alleles and have confirmed their colonization phenotypes by using competition experiments and by determining the dose required for 50% infection. Of the genetic loci retested, 60% have strain-specific colonization defects, while 40% have phenotypes in both strain backgrounds for infection, highlighting the profound effect of H. pylori strain variation on the pathogenic potential of this organism.Helicobacter pylori, a bacterial pathogen of the human stomach, infects an estimated 50% of the population worldwide. Infection by H. pylori causes gastritis initially and, if allowed to persist, can induce a range of pathologies. It is the causative agent of most peptic ulcers, and other serious outcomes such as atrophic gastritis, intestinal metaplasia, and gastric cancer are correlated with long-term infections. It is not yet known whether these outcomes are due to specific factors produced by the organism or whether they result from chronic inflammation due to efficient and persistent colonization of the gastric mucosa. Thus, colonization and persistence factors may themselves constitute virulence factors for this organism.

DNA transfer in the gastric pathogen Helicobacter pylori

“…This conservation is in agreement with the need for genomic fluidity, enabling the bacteria to keep the gene content flexible and as diverse as possible to survive in the stomach during the lifelong colonization and infection process. In agreement with this assumption, the comB4 and comB3 genes have been identified in transposon mutant library screens to be essential for colonization in gerbils and mice, respectively [48,49]. This suggests that natural competence may indeed play a role in host colonization.…”

Diverse Functions of Restriction-Modification Systems in Addition to Cellular Defense

“…These genes might help the organism adapt to an acidic environment (205). Similarly, an analysis of the H. pylori transcriptome profile in infected mice resulted in the identification of several R-M genes that contribute to the colonization of the gut (206). These studies point toward a role for R-M systems in the adaptation of the bacteria to hostile environments.…”

Rapid evolution of distinctHelicobacter pylorisubpopulations in the Americas

“…Together with AlpA, it is required for colonization in experimental models and for efficient adhesion to gastric epithelial cells [24]. The HofC protein is also required for H. pylori colonization in mice and gerbils [25,26] is not well characterized and little is known about its function. TlpA and FrpB4 are important in the bacterial adaptation to variation in the microenvironment.…”