Helicobacter pylorigenetic diversification in the Mongolian gerbil model

Abstract

Helicobacter pylori requires genetic agility to infect new hosts and establish long-term colonization of changing gastric environments. In this study, we analyzed H. pylori genetic adaptation in the Mongolian gerbil model. This model is of particular interest because H. pylori-infected gerbils develop a high level of gastric inflammation and often develop gastric adenocarcinoma or gastric ulceration. We analyzed the whole genome sequences of H. pylori strains cultured from experimentally infected gerbils, in comparison to the genome sequence of the input strain. The mean annualized single nucleotide polymorphism (SNP) rate per site was 1.5e−5, which is similar to the rates detected previously in H. pylori-infected humans. Many of the mutations occurred within or upstream of genes associated with iron-related functions (fur, tonB1, fecA2, fecA3, and frpB3) or encoding outer membrane proteins (alpA, oipA, fecA2, fecA3, frpB3 and cagY). Most of the SNPs within coding regions (86%) were non-synonymous mutations. Several deletion or insertion mutations led to disruption of open reading frames, suggesting that the corresponding gene products are not required or are deleterious during chronic H. pylori colonization of the gerbil stomach. Five variants (three SNPs and two deletions) were detected in isolates from multiple animals, which suggests that these mutations conferred a selective advantage. One of the mutations (FurR88H) detected in isolates from multiple animals was previously shown to confer increased resistance to oxidative stress, and we now show that this SNP also confers a survival advantage when H. pylori is co-cultured with neutrophils. Collectively, these analyses allow the identification of mutations that are positively selected during H. pylori colonization of the gerbil model.

Genome-wide mutation analysis of Helicobacter pylori after inoculation to Mongolian gerbils

“…Mutations in oppA and tlpB have also been reported [19] (Table 2), but the inoculated animal in this study was a mouse. There were no genes in common with another genome study using the Mongolian gerbil as a model [16]. Another research group compared the H. pylori genome before (PMSS1) and after (SS1) inoculation [19].…”

“…However, H. pylori is well adapted to the human stomach but does not easily infect other animals. In search of a good animal model, experimental infection was attempted in Rhesus monkeys [9], mice [10], and Mongolian gerbils [11–16]. Genetic diversification of H. pylori in the infected animals was also studied [9, 10, 16–19].…”

“…Earlier studies used PCR to investigate changes in genes during animal infection. However, DNA sequencing advancements enabled the extensive exploration of mutations by sequencing bacterial genomes before and after infection [16, 19]. Here, we used the whole genome sequence of TN2 wild type (TN2wt) as a reference and sequenced short reads from three derivative strains to identify genomic mutations during infection in Mongolian gerbils.…”

Hydrogen Peroxide-Mediated Oxygen Enrichment Eradicates Helicobacter pylori In Vitro and In Vivo

“…In addition to these experiments in vitro, we also verified the effect of hydrogen peroxide on H. pylori in vivo. Mongolian gerbils are the most commonly used animal for establishing an H. pylori-infection model (37,38). The symptoms of H. pylori-infected gerbils, such as the loss of appetite and weight, were consistent with human patients.…”

Genome-wide association study of gastric cancer- and duodenal ulcer-derivedHelicobacter pyloristrains reveals discriminatory amino acid differences and novel oncoprotein candidates

“…A large part of the fecA-2 gene is deleted in hspAmerind strains. Mutations in fecA-2 have been observed after H. pylori diversification in the Mongolian gerbil (Beckett, et al 2018).…”