Rapid evolution of the Helicobacter pylori AlpA adhesin in a high gastric cancer risk region from Colombia.
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ABSTRACT:
SUBMITTER: Gutierrez-Escobar AJ
PROVIDER: S-EPMC5971833 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC6507892 | biostudies-literature
Project description:Helicobacter pylori persistently colonizes humans, causing gastritis, ulcers, and gastric cancer. Adherence to the gastric epithelium has been shown to enhance inflammation, yet only a few H. pylori adhesins have been paired with targets in host tissue. The alpAB locus has been reported to encode adhesins involved in adherence to human gastric tissue. We report that abrogation of H. pylori AlpA and AlpB reduces binding of H. pylori to laminin while expression of plasmid-borne alpA or alpB confers laminin-binding ability to Escherichia coli. An H. pylori strain lacking only AlpB is also deficient in laminin binding. Thus, we conclude that both AlpA and AlpB contribute to H. pylori laminin binding. Contrary to expectations, the H. pylori SS1 mutant deficient in AlpA and AlpB causes more severe inflammation than the isogenic wild-type strain in gerbils. Identification of laminin as the target of AlpA and AlpB will facilitate future investigations of host-pathogen interactions occurring during H. pylori infection.
| S-EPMC3147585 | biostudies-literature
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.
| S-EPMC6249973 | biostudies-literature
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.
| S-EPMC4345146 | biostudies-literature
Project description:BackgroundA recent report has shown that the phylogenetic origin of Helicobacter pylori based on multi-locus sequence typing (MLST) was significantly associated with the severity of gastritis in Colombia. However, the potential relationship between phylogenetic origin and clinical outcomes was not examined in that study. If the phylogenetic origin rather than virulence factors were truly associated with clinical outcomes, identifying a population at high risk for gastric cancer in Colombia would be relatively straightforward. In this study, we examined the phylogenetic origins of strains from gastric cancer and duodenal ulcer patients living in Bogota, Colombia.MethodsWe included 35 gastric cancer patients and 31 duodenal ulcer patients, which are considered the variant outcomes. The genotypes of cagA and vacA were determined by polymerase chain reaction. The genealogy of these Colombian strains was analyzed by MLST. Bacterial population structure was analyzed using STRUCTURE software.ResultsH. pylori strains from gastric cancer and duodenal ulcer patients were scattered in the phylogenetic tree; thus, we did not detect any difference in phylogenetic distribution between gastric cancer and duodenal ulcer strains in the hpEurope group in Colombia. Sixty-six strains, with one exception, were classified as hpEurope irrespective of the cagA and vacA genotypes, and type of disease. STRUCTURE analysis revealed that Colombian hpEurope strains have a phylogenetic connection to Spanish strains.ConclusionsOur study showed that a phylogeographic origin determined by MLST was insufficient for distinguishing between gastric cancer and duodenal ulcer risk among hpEurope strains in the Andean region in Colombia. Our analysis also suggests that hpEurope strains in Colombia were primarily introduced by Spanish immigrants.
| S-EPMC4133377 | biostudies-literature
Project description:For the last 500 years, the Americas have been a melting pot both for genetically diverse humans and for the pathogenic and commensal organisms associated with them. One such organism is the stomach-dwelling bacterium Helicobacter pylori, which is highly prevalent in Latin America where it is a major current public health challenge because of its strong association with gastric cancer. By analyzing the genome sequence of H. pylori isolated in North, Central and South America, we found evidence for admixture between H. pylori of European and African origin throughout the Americas, without substantial input from pre-Columbian (hspAmerind) bacteria. In the US, strains of African and European origin have remained genetically distinct, while in Colombia and Nicaragua, bottlenecks and rampant genetic exchange amongst isolates have led to the formation of national gene pools. We found three outer membrane proteins with atypical levels of Asian ancestry in American strains, as well as alleles that were nearly fixed specifically in South American isolates, suggesting a role for the ethnic makeup of hosts in the colonization of incoming strains. Our results show that new H. pylori subpopulations can rapidly arise, spread and adapt during times of demographic flux, and suggest that differences in transmission ecology between high and low prevalence areas may substantially affect the composition of bacterial populations.
| S-EPMC5322909 | biostudies-literature
Project description:The present study concerns the identification of a novel coding sequence in a region of the Helicobacter pylori genome, located between JHP1069/HP1141 and JHP1071/HP1143 according to the numbering of the J99 and 26,695 reference strains, respectively, and spanning three different coding DNA sequences (CDSs). The CDSs located at the centre of this locus were highly polymorphic, as determined by the analysis of 24 European isolates, 3 Asian, and 3 African isolates. Phylogenetic and molecular evolutionary analyses showed that the CDSs were not restricted to the geographical origin of the strains. Despite a very high variability observed in the deduced protein sequences, significant similarity was observed, always with the same protein families, i.e. ATPase and bacteriophage receptor/invasion proteins. Although this variability could be explained by isotopic gene replacement via horizontal transfer of a gene with the same function but coming from a variety of sources, it seems more likely that the very high sequence variation observed at this locus is the result of a strong selection pressure exerted on the corresponding gene product. The CDSs identified in the present study could be used as strain specific markers.
| S-EPMC2650637 | biostudies-literature
Project description:Persistent colonization of the human stomach with Helicobacter pylori is a risk factor for gastric adenocarcinoma, and H. pylori-induced carcinogenesis is dependent on the actions of a bacterial oncoprotein known as CagA. Epidemiological studies have shown that high dietary salt intake is also a risk factor for gastric cancer. To investigate the effects of a high-salt diet, we infected Mongolian gerbils with a wild-type (WT) cagA(+) H. pylori strain or an isogenic cagA mutant strain and maintained the animals on a regular diet or a high-salt diet. At 4 months postinfection, gastric adenocarcinoma was detected in 100% of the WT-infected/high-salt-diet animals, 58% of WT-infected/regular-diet animals, and none of the animals infected with the cagA mutant strain (P < 0.0001). Among animals infected with the WT strain, those fed a high-salt diet had more severe gastric inflammation, higher gastric pH, increased parietal cell loss, increased gastric expression of interleukin 1? (IL-1?), and decreased gastric expression of hepcidin and hydrogen potassium ATPase (H,K-ATPase) compared to those on a regular diet. Previous studies have detected upregulation of CagA synthesis in response to increased salt concentrations in the bacterial culture medium, and, concordant with the in vitro results, we detected increased cagA transcription in vivo in animals fed a high-salt diet compared to those on a regular diet. Animals infected with the cagA mutant strain had low levels of gastric inflammation and did not develop hypochlorhydria. These results indicate that a high-salt diet potentiates the carcinogenic effects of cagA(+) H. pylori strains.
| S-EPMC3676043 | biostudies-literature
Project description:Gastric cancer still is a major concern as the third most common cancer worldwide, despite declining rates of incidence in many Western countries. Helicobacter pylori (H. pylori) is the major cause of gastric carcinogenesis, and its infection insults gastric mucosa leading to the occurrence of atrophic gastritis which progress to intestinal metaplasia, dysplasia, early gastric cancer, and advanced gastric cancer consequently. This review focuses on multiple factors including microbial virulence factors, host genetic factors, and environmental factors, which can heighten the chance of occurrence of gastric adenocarcinoma due to H. pylori infection. Bacterial virulence factors are key components in controlling the immune response associated with the induction of carcinogenesis, and cagA and vacA are the most well-known pathogenic factors. Host genetic polymorphisms contribute to regulating the inflammatory response to H. pylori and will become increasingly important with advancing techniques. Environmental factors such as high salt and smoking may also play a role in gastric carcinogenesis. It is important to understand the virulence factors, host genetic factors, and environmental factors interacting in the multistep process of gastric carcinogenesis. To conclude, prevention via H. pylori eradication and controlling environmental factors such as diet, smoking, and alcohol is an important strategy to avoid H. pylori-associated gastric carcinogenesis.
| S-EPMC4678392 | biostudies-literature
Project description:Genetic analysis and culturing techniques for gastric non-Helicobacter pylori Helicobacter (NHPH) are progressing. NHPH is reported to accompany nodular gastritis, gastric MALT lymphoma, and mild gastritis. However, only a few gastric cancer cases infected by NHPH have been reported. PCR analysis specific for NHPH and H. pylori was performed for DNA from gastric mucosa of 282 Korean gastric cancer patients, who were treated with endoscopic submucosal dissection. For more precise strain detection of NHPH, NHPH-positive mucosa was stained by immunohistochemistry specific for Helicobacter suis. The Cancer Genome Atlas (TCGA) classification was analyzed for these 3 gastric cancer sub-groups by in situ hybridization and immunohistochemistry. Among 281 patients, 3 patients (1.1%) were positive for NHPH. One patient (Patient 1) was also positive for H. pylori by PCR, another patient (Patient 3) was positive for serum IgG for H. pylori, and the other patient (Patient 2) had no evidence for H. pylori infection. Gastric mucosa of Patients 2 and 3 were positive for H. suis staining. All three NHPH-positive gastric cancers were located in the antrum, and belonged to the Chromosomal Instability Type of TCGA classification. Gastric NHPH can be a cause of gastric cancer, although likely with lower pathogenesis than H. pylori.
| S-EPMC8938428 | biostudies-literature