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Rapid evolution of the Helicobacter pylori AlpA adhesin in a high gastric cancer risk region from Colombia.

ABSTRACT: To be able to survive, Helicobacter pylori must adhere to the gastric epithelial cells of its human host. For this purpose, the bacterium employs an array of adhesins, for example, AlpA. The adhesin AlpA has been proposed as a major adhesin because of its critical role in human stomach colonization. Therefore, understanding how AlpA evolved could be important for the development of new diagnostic strategies. However, the genetic variation and microevolutionary patterns of alpA have not been described in Colombia. The study aim was to describe the variation patterns and microevolutionary process of alpA in Colombian clinical isolates of H. pylori. The existing polymorphisms, which are deviations from the neutral model of molecular evolution, and the genetic differentiation of the alpA gene from Colombian clinical isolates of H. pylori were determined. The analysis shows that gene conversion and purifying selection have shaped the evolution of three different variants of alpA in Colombia.

SUBMITTER: Gutierrez-Escobar AJ

PROVIDER: S-EPMC5971833 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Rapid evolution of the Helicobacter pylori AlpA adhesin in a high gastric cancer risk region from Colombia.

Gutiérrez-Escobar Andrés Julián AJ Méndez-Callejas Gina G Acevedo Orlando O Bravo Maria Mercedes MM

PeerJ 20180525

To be able to survive, Helicobacter pylori must adhere to the gastric epithelial cells of its human host. For this purpose, the bacterium employs an array of adhesins, for example, AlpA. The adhesin AlpA has been proposed as a major adhesin because of its critical role in human stomach colonization. Therefore, understanding how AlpA evolved could be important for the development of new diagnostic strategies. However, the genetic variation and microevolutionary patterns of alpA have ...[more]

PMID: 29844987

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Project description:The stomach bacterium Helicobacter pylori is one of the most prevalent pathogens in humans, closely linked with serious diseases such as gastric cancer. The microbe has been associated with its host for more than 100,000 years and escorted modern humans out of Africa. H. pylori is predominantly transmitted within families and dispersed globally, resulting in distinct phylogeographic patterns, which can be utilized to investigate migrations and bioturbation events in human history. Latin America was affected by several human migratory waves due to the Spanish colonisation that drastically changed the genetic load and composition of the bacteria and its host. Genetic evidence indicates that independent evolutionary lines of H. pylori have evolved in mestizos from Colombia and other countries in the region during more than 500 years since colonisation. The vacuolating cytotoxin VacA represents a major virulence factor of the pathogen comprising two domains, p33 and p55, the latter of which is essential for binding to the host epithelial cell. The evolution of the VacA toxin in Colombia has been strongly biased due to the effects of Spanish colonization. However, the variation patterns and microevolution of the p55 domain have not yet been described for this population. In the present study, we determined the genetic polymorphisms and deviations in the neutral model of molecular evolution in the p55 domain of 101 clinical H. pylori isolates collected in Bogotá, a city located in Andean mountains characterized by its high gastric cancer risk and its dominant mestizo population. The microevolutionary patterns of the p55 domain were shaped by recombination, purifying and episodic diversifying positive selection. Furthermore, amino acid positions 261 and 321 in the p55 domain of VacA show a high variability among mestizos clinical subsets, suggesting that natural selection in H. pylori may operate differentially in patients with different gastric diseases.

Project description:BackgroundHelicobacter pylori is a human stomach pathogen, naturally-competent for DNA uptake, and prone to homologous recombination. Extensive homoplasy (i.e., phylogenetically-unlinked identical variations) observed in H. pylori genes is considered a hallmark of such recombination. However, H. pylori also exhibits a high mutation rate. The relative adaptive role of homologous recombination and mutation in species diversity is a highly-debated issue in biology. Recombination results in homoplasy. While convergent mutation can also account for homoplasy, its contribution is thought to be minor. We demonstrate here that, contrary to dogma, convergent mutation is a key contributor to Helicobacter pylori homoplasy, potentially driven by adaptive evolution of proteins.ResultsOur present genome-wide analysis shows that homoplastic nonsynonymous (amino acid replacement) changes are not typically accompanied by homoplastic synonymous (silent) variations. Moreover, the majority of the codon positions with homoplastic nonsynonymous changes also contain different (i.e. non-homoplastic) nonsynonymous changes arising from mutation only. This indicates that, to a considerable extent, nonsynonymous homoplasy is due to convergent mutations. High mutation rate or limited availability of evolvable sites cannot explain this excessive convergence, as suggested by our simulation studies. Rather, the genes with convergent mutations are overrepresented in distinct functional categories, suggesting possible selective responses to conditions such as distinct micro-niches in single hosts, and to differences in host genotype, physiology, habitat and diet.ConclusionsWe propose that mutational convergence is a key player in H. pylori's adaptation and extraordinary persistence in human hosts. High frequency of mutational convergence could be due to saturation of evolvable sites capable of responding to selection pressures, while the number of mutable residues is far from saturation. We anticipate a similar scenario of mutational vs. recombinational genome dynamics or plasticity for other naturally competent microbes where strong positive selection could favor frequent convergent mutations in adaptive protein evolution.

Project description:Helicobacter pylori infection causes gastric cancer, the third leading cause of cancer death worldwide. More than half of the world's population is infected, making universal eradication impractical. Clinical trials suggest that antibiotic treatment only reduces gastric cancer risk in patients with non-atrophic gastritis (NAG), and is ineffective once preneoplastic lesions of multifocal atrophic gastritis (MAG) and intestinal metaplasia (IM) have occurred. Therefore, additional strategies for risk stratification and chemoprevention of gastric cancer are needed. We have implicated polyamines, generated by the rate-limiting enzyme ornithine decarboxylase (ODC), in gastric carcinogenesis. During H. pylori infection, the enzyme spermine oxidase (SMOX) is induced, which generates hydrogen peroxide from the catabolism of the polyamine spermine. Herein, we assessed the role of SMOX in the increased gastric cancer risk in Colombia associated with the Andean mountain region when compared with the low-risk region on the Pacific coast. When cocultured with gastric epithelial cells, clinical strains of H. pylori from the high-risk region induced more SMOX expression and oxidative DNA damage, and less apoptosis than low-risk strains. These findings were not attributable to differences in the cytotoxin-associated gene A oncoprotein. Gastric tissues from subjects from the high-risk region exhibited greater levels of SMOX and oxidative DNA damage by immunohistochemistry and flow cytometry, and this occurred in NAG, MAG and IM. In Mongolian gerbils, a prototype colonizing strain from the high-risk region induced more SMOX, DNA damage, dysplasia and adenocarcinoma than a colonizing strain from the low-risk region. Treatment of gerbils with either α-difluoromethylornithine, an inhibitor of ODC, or MDL 72527 (N(1),N(4)-Di(buta-2,3-dien-1-yl)butane-1,4-diamine dihydrochloride), an inhibitor of SMOX, reduced gastric dysplasia and carcinoma, as well as apoptosis-resistant cells with DNA damage. These data indicate that aberrant activation of polyamine-driven oxidative stress is a marker of gastric cancer risk and a target for chemoprevention.

Dataset Information

Rapid evolution of the Helicobacter pylori AlpA adhesin in a high gastric cancer risk region from Colombia.

Publications

Rapid evolution of the <i>Helicobacter pylori</i> AlpA adhesin in a high gastric cancer risk region from Colombia.

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