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  • Review Article
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Helicobacter pylori evolution and phenotypic diversification in a changing host

Nature Reviews Microbiology volume 5, pages 441–452 (2007)Cite this article

Key Points

  • The human gastric pathogen Helicobacter pylori displays a high degree of intraspecies allelic diversity and variability. Almost every infected person carries one or multiple unique H. pylori strains that can be readily distinguished by MLST or other typing methods.

  • Diversity within H. pylori is generated by the unusual combination of an elevated mutation rate and frequent interstrain recombination during mixed infections. Unusually short DNA fragments are incorporated into the H. pylori genome in the course of recombination events, further contributing to allelic diversification.

  • Modern H. pylori bacteria can be subdivided into six main populations with distinct geographic distribution patterns. These modern populations are derived from five ancestral populations, and the distribution of ancestral nucleotides over the globe reflects ancient and more recent human migrations.

  • Many H. pylori genes contain hypermutable sequences, such as homopolymeric nucleotide repeats. Any large H. pylori population will therefore consist of multiple subpopulations with specific activity patterns for these so-called contingency genes (bacterial quasispecies).

  • Genetic variability that is due to intrastrain diversification and interstrain recombination is hypothesized to help the bacteria adapt to individual hosts after transmission. Although experimental evidence is still scarce, this concept is supported by the finding that extensive genetic and phenotypic variation is displayed by molecules involved in interactions with the human host, including adhesins, lipopolysaccharides and components of the cag type IV secretion apparatus, including the translocated effector CagA.

Abstract

Helicobacter pylori colonizes the stomachs of more than 50% of the world's population, making it one of the most successful of all human pathogens. One striking characteristic of H. pylori biology is its remarkable allelic diversity and genetic variability. Not only does almost every infected person harbour their own individual H. pylori strain, but strains can undergo genetic alteration in vivo, driven by an elevated mutation rate and frequent intraspecific recombination. This genetic variability, which affects both housekeeping and virulence genes, has long been thought to contribute to host adaptation, and several recently published studies support this concept. We review the available knowledge relating to the genetic variation of H. pylori, with special emphasis on the changes that occur during chronic colonization, and argue that H. pylori uses mutation and recombination processes to adapt to its individual host by modifying molecules that interact with the host. Finally, we put forward the hypothesis that the lack of opportunity for intraspecies recombination as a result of the decreasing prevalence of H. pylori could accelerate its disappearance from Western populations.

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Figure 1: Helicobacter pylori and its extensive genetic heterogeneity.
Figure 2: Helicobacter pylori populations and their worldwide distribution.
Figure 3: The effect of mutation and recombination on sequences during chronic infection.
Figure 4: The cag pathogenicity island contains genes that show marked sequence variation.

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Acknowledgements

The authors wish to dedicate this article to their long-time academic teacher and mentor, W. Opferkuch, on the occasion of his 75th birthday. M. Achtman and D. Falush are acknowledged for many fruitful discussions on bacterial evolution. We also thank three anonymous reviewers for helpful suggestions. Work in the authors' laboratories was supported by grants from the German Research Foundation (DFG), the German Ministry for Education and Research (Competence network PathoGenoMik and ERA-NET Pathogenomics - HELDIVNET), the European Commission (FP6 Integrated Project INCA) and the Volkswagen Foundation.

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  1. Medizinische Hochschule Hannover, Institut für Medizinische Mikrobiologie und Krankenhaushygiene, Carl-Neuberg-Strasse 1, Hannover, 30625, Germany

    Sebastian Suerbaum & Christine Josenhans

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DATABASES

Entrez Genome Project

Escherichia coli

Helicobacter hepaticus

Helicobacter pylori

Helicobacter pylori HPAG1

Helicobacter pylori J99

Helicobacter pylori 26695

FURTHER INFORMATION

MLST databases

Structure software

Glossary

RAPD

(Random amplification of polymorphic DNA). A simple method to assess the genetic relatedness of bacterial strains within one species. A single short primer is used in PCR reactions and the resulting band patterns are compared.

Microevolution

The generation of genetic variation within a species over relatively short timescales.

Polymorphic nucleotide

A position in a nucleotide sequence that displays variation in a sample population. If a sequence analysis of a gene fragment for n isolates yields three different alleles, for example, AACTTA, AAGTTA and AAATTA, the third position in this sequence is polymorphic but the other positions are not.

Multilocus enzyme electrophoresis

(MLEE). A classical method that was used to study the structure of bacterial populations. Differences between the electrophoretic mobilities of multiple enzymes in starch gels are used as indicators of allelic variation.

Homoplasy test

A method to quantify the contribution of recombination to sequence variation in a set of homologous nucleotide sequences from multiple isolates.

Panmictic

A population structure where clonal structure is lost due to frequent recombination. Species with panmictic or close to panmictic population structures include Helicobacter pylori and Neisseria gonorrhoeae; species with predominantly clonal population structures include Salmonella enterica and Mycobacterium tuberculosis.

Type IV secretion system

(T4SS). A complex bacterial secretion system that can transport bacterial protein effector molecules or DNA into a eukaryotic cell.

MLST

(Multilocus sequence typing). A nucleotide-sequence-based approach for the characterization of isolates of microorganisms. The method involves the sequence analysis of approximately seven housekeeping gene fragments. Unique sequences obtained for each fragment are assigned an allele number, and the combination of allele numbers for all fragments defines the sequence type (ST). MLST is applicable to almost all bacteria and some other microorganisms. See Further information for a central website to access MLST databases for different organisms.

Autosomal microsatellite marker

A microsatellite is a simple sequence repeat that consists of repeating units of 1–4 nucleotides. Microsatellites are highly polymorphic and are widely used as markers in human genetic studies. The term autosomal is used if a microsatellite marker is located on a non-sex chromosome (in contrast to markers located on X or Y chromosomes).

Mutator strain

A strain of a bacterial species that has an elevated mutation rate compared with the average mutation rate of the species. The mutator phenotype is due to defects in genes coding for DNA repair enzymes or proteins involved in assuring fidelity of DNA replication.

Mismatch repair

(MMR). A DNA repair mechanism that recognizes and corrects mismatches between the parental DNA strand and the copied DNA strand that is generated during replication.

Base excision repair

(BER). A DNA repair mechanism that recognizes and corrects single mutated bases in the DNA, such as oxidated or alkylated bases.

Pyrosequencing

A sequencing method that is based on the detection of released pyrophosphate (PPi) during DNA synthesis.

T helper (TH) 1 immune response

T cell immune responses can be broadly categorized into two types. TH1 responses are dominated by TH1 cells, which produce interferon-γ and tumour necrosis factor. TH2 responses are characterized by a prodominance of TH2 cells secreting interleukins (IL)-4, IL-5 and IL-13. The TH1 response is particularly geared towards the defence against intracellular bacteria, whereas the TH2 response is more suited to defend against extracellular bacteria.

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Suerbaum, S., Josenhans, C. Helicobacter pylori evolution and phenotypic diversification in a changing host. Nat Rev Microbiol 5, 441–452 (2007). https://doi.org/10.1038/nrmicro1658

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