Molecular epidemiology, population genetics, and pathogenic role of Helicobacter pylori

Abstract

Helicobacter pylori infection is linked to various gastroduodenal diseases; however, only approximately 20% of infected individuals develop severe diseases. Despite the high prevalence of H. pylori infection in Africa and South Asia, the incidence of gastric cancer in these areas is much lower than in other countries. Furthermore, the incidence of gastric cancer tends to decrease from north to south in East Asia. Such geographic differences in the pathology can be explained, at least in part, by the presence of different types of H. pylori virulence factors, especially cagA, vacA, and the right end of the cag pathogenicity island. The genotype of the virulence genes is also useful as a tool to track human migration utilizing the high genetic diversity and frequent recombination between different H. pylori strains. Multilocus sequence typing (MLST) analysis using seven housekeeping genes can also help to predict the history of human migrations. Population structure analysis based on MLST has revealed seven modern population types of H. pylori, which derived from six ancestral populations. Interestingly, the incidence of gastric cancer is closely related to the distribution of H. pylori populations. The different incidence of gastric cancer can be partly attributed to the different genotypes of H. pylori circulating in different geographic areas. Although approaches by MLST and virulence factors are effective, these methods focus on a small number of genes and may miss information conveyed by the rest of the genome. Genome-wide analyses using DNA microarray or whole-genome sequencing technology give a broad view on the genome of H. pylori. In particular, next-generation sequencers, which can read DNA sequences in less time and at lower costs than Sanger sequencing, enabled us to efficiently investigate not only the evolution of H. pylori, but also novel virulence factors and genomic changes related to drug resistance.

Figure 1. Helicobacter pylori populations and phylogenetic tree

Phylogenetic tree constructed by using multilocus sequence typing (MLST) data (neighbor-joining [NJ]-tree, Kimura 2 parameter). Branch colors represent H. pylori populations determined by using the Bayesian clustering method. hspSAfrica and hspWAfrica are subpopulations of hpAfrica1 and hspAmerind, hspMaori, and hspEAsia are subpopulations of hpEastAsia.

Figure 2. Schematic representation of the vacA alleles

The vacA s1 genotype has a 27-bp deletion as compared to the s2 genotype. The vacA i region can be classified into 2 types (i1 and i2, shaded in orange and red, respectively) according to the amino acid sequences denoted as clusters A, B, and C (from left to right). The vacA d2 genotype has a 69- to 81-bp deletion as compared to the d1 genotype. The vacA m1 genotype has a 73-bp deletion as compared to the m2 genotype.

Figure 3. Geographic distribution of Helicobacter pylori populations and predicted traces of prehistoric human migration

Colored circles illustrate the putative distribution of H. pylori populations before the “Age of Exploration.” Black arrows and numbers represent predicted paths and times of migration.

Figure 4. Phylogenetic trees by using multilocus sequence typing (MLST) data and concatenated genes

Phylogenetic trees (neighbor-joining [NJ]-tree, Kimura 2 parameter, bootstrap 1000) (A) by using MLST data and (B) by using concatenated genes (~1 Mb). Red numbers indicate bootstrap values greater than 60%.