A Global Overview of the Genetic and Functional Diversity in the Helicobacter pylori cag Pathogenicity Island

Olbermann, Patrick; Josenhans, Christine; Moodley, Yoshan; Uhr, M.; Stamer, Christiana; Vauterin, Marc; Suerbaum, Sebastian; Achtman, Mark; Linz, Bodo

doi:10.1371/journal.pgen.1001069

Cited by 199 publications

(272 citation statements)

References 61 publications

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“…We identified a number of putatively selected vacA genes in local populations as expected from previous indications of their importance in H. pylori pathogenicity (Olbermann et al 2010). It is further interesting to note that vacA and vacA-like genes also show evidence for selection among African populations, where the association of H. pylori with gastric disease is not considered to be significant.…”

Section: Genes Involved In Virulencesupporting

confidence: 73%

Worldwide Population Structure, Long-Term Demography, and Local Adaptation of Helicobacter pylori

et al. 2015

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Helicobacter pylori is an important human pathogen associated with serious gastric diseases. Owing to its medical importance and close relationship with its human host, understanding genomic patterns of global and local adaptation in H. pylori may be of particular significance for both clinical and evolutionary studies. Here we present the first such whole genome analysis of 60 globally distributed strains, from which we inferred worldwide population structure and demographic history and shed light on interesting global and local events of positive selection, with particular emphasis on the evolution of San-associated lineages. Our results indicate a more ancient origin for the association of humans and H. pylori than previously thought. We identify several important perspectives for future clinical research on candidate selected regions that include both previously characterized genes (e.g., transcription elongation factor NusA and tumor necrosis factor alpha-inducing protein Tipa) and hitherto unknown functional genes.KEYWORDS adaptation; neutral evolution; human pathogens H ELICOBACTER pylori is a Gram-negative bacterium that infects the mucosa of the human stomach. It was first described in the 1980s, when it was initially identified in association with chronic gastritis and later causally linked to serious gastric pathologies such as gastric cancer and ulcers (Marshall and Warren 1984;Suerbaum and Michetti 2002). It infects .80% of humans in developing countries and, although its prevalence is lower in developed countries, nearly 50% of the worldwide human population is infected (Ghose et al. 2005;Salih 2009;Salama et al. 2013).Due to its clinical and evolutionary importance, there has been considerable research on mechanisms of H. pylori transmission, as well as on the population genetics and phylogenetic relationships among global isolates. Thus far, population genetic analyses have mainly focused on seven housekeeping genes (usually referred to as multilocus sequence typing or MLST), with the primary conclusions being that H. pylori strains appear highly structured, and their phylogeographic patterns correlate consistently with that of their human hosts. Given that the H. pylori-humans association is at least 100,000 years old (Moodley et al. 2012), the current population structure of H. pylori may be regarded as mirroring past human expansions and migrations Linz et al. 2007;Breurec et al. 2011) and thus help us shed light on yet unknown dynamics of local demographic processes in human evolution. However, despite the knowledge gained thus far, the long-term global demographic history of H. pylori has never been directly inferred. The long, intimate association of H. pylori with humans suggests a history of bacterial adaptation. Considerable attention has focused on specific genes involved in modulating adaptive immunity of the host (for a review see Yamaoka 2010 andSalama et al. 2013) and on genomic changes occurring during acute and chronic H. pylori infection (Kennemann et al. 2011;Linz et a...

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Section: Genes Involved In Virulencesupporting

confidence: 73%

Worldwide Population Structure, Long-Term Demography, and Local Adaptation of Helicobacter pylori

et al. 2015

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“…The existence of 7 different genotypes of cagPAI among the 12 studied strains confirmed a high rate of diversity in this genetic locus, which may correlate with pathogenicity of the strains. Ahmadzadeh et al represented 13 different cagPAI genotyptes among 21 cagPAI positive H. pylori strains in Iran (34).This diversity is also high in different geographic populations (11,(35)(36)(37). Correlation between integrity of cagPAI, types of EPIYA motifs, and disease outcome was confirmed by several studies (24,(38)(39)(40)(41)(42).…”

Section: Discussionmentioning

confidence: 88%

Functional Cytotoxin Associated Gene A in Helicobacter pylori Strains and Its Association with Integrity of Cag-pathogenicity Island and Histopathological Changes of Gastric Tissue

Fazeli

Alebouyeh

Tavirani

et al. 2017

Arch Clin Infect Dis

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Objectives: Existence of cytotoxin associated gene A (cagA) is considered as a marker for detection of an oncogenic Helicobacter pylori strain. Expression of cagA in the strains with incomplete delivery system (partial CagPAI) could convert them to less virulent strains.This study was aimed to analyze expression of cagA in H. pylori strains presenting diverse cagPAI and its effect on histopathological changes of the gastric tissue. Methods: Clinical strains of H. pylori and related histopathological data were obtained to examine the presence of 12 cagPAI segments by PCR. Expression of cagA was analyzed by RT-PCR as well as Immunoblotting on RNA and protein extracts of the cagPAIpositive strains, respectively. In situe expression of CagA-positive strains was determined in a gastric epithelial cell line. Results: Intact cagPAI was detected among 33% (4/12) of H. pylori strains. Out of 7 diverse cagPAI genotypes in these strains, expression of cagA was confirmed in 2 strains with complete cagPAI at both RNA and protein levels. Occurrence of intestinal metaplasia and severe active gastritis were mainly detected in the strains with complete cagPAI genotype. No association was detected between EPIYA types of the strains and expression of cagA. Conclusions: These results collectively showed high diversity of cagA and cagPAI among the H. pylori strains. These diversities may provide some reasons to explain distinct disease severity caused by different H. pylori strains in the gastric tissue.

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“…Therefore, CagA has been recognized as a genetic marker for the cagPAI locus [29] and H. pylori-associated disease development [1,2]. Sequence comparison of the cagPAI genes of more than 30 H. pylori isolates have shown that the gene order and content are highly conserved [30]. The phylogeny of most cagPAI genes was similar to that of housekeeping genes, indicating that it was acquired by a single event more than 60,000 years ago, and its genetic diversity reflects the isolation by distance that has shaped this bacterial species since modern humans migrated out of Africa [30].…”

Section: General Role Of Type IV Secretion Systems (T4sss) In Dna Excmentioning

confidence: 99%

“…Sequence comparison of the cagPAI genes of more than 30 H. pylori isolates have shown that the gene order and content are highly conserved [30]. The phylogeny of most cagPAI genes was similar to that of housekeeping genes, indicating that it was acquired by a single event more than 60,000 years ago, and its genetic diversity reflects the isolation by distance that has shaped this bacterial species since modern humans migrated out of Africa [30]. The fact that the 40 kb cagPAI has been incorporated by an ancient DNA transfer episode represents a remarkable example for its importance in acquiring genetic elements for bacterial virulence.…”

Section: General Role Of Type IV Secretion Systems (T4sss) In Dna Excmentioning

confidence: 99%

DNA transfer in the gastric pathogen Helicobacter pylori

Fernández-González

Backert

2014

J Gastroenterol

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The gastric pathogen Helicobacter pylori is one of the most genetically diverse bacteria. Recombination and DNA transfer contribute to its genetic variability and enhance host adaptation. Among the strategies described to increase genetic diversity in bacteria, DNA transfer by conjugation is one of the best characterized. Using this mechanism, a fragment of DNA from a donor cell can be transferred to a recipient, always mediated by a conjugative nucleoprotein complex, which is evolutionarily related to type IV secretion systems (T4SSs). Interestingly, the H. pylori chromosomes can encode up to four T4SSs, including the cagPAI, comB, tfs3, and tfs4 genes, some of which are known to promote chronic H. pylori infection. The T4SS encoded by the cagPAI mediates the injection of the effector protein CagA and proinflammatory signaling, and the comB system is involved in DNA uptake from the environment. However, the role of tfs3 and tfs4 is not yet clear. The presence of a functional XerD tyrosine recombinase and 5 0 AAAGAATG-3 0 border sequences as well as two putative conjugative relaxases (Rlx1 and Rlx2), a coupling protein (TraG), and a chromosomal region carrying a putative origin of transfer (oriT) suggest the existence of a DNA transfer apparatus in tfs4. Moreover, a conjugation-like DNA transfer mechanism in H. pylori has already been described in vitro, but whether this occurs in vivo is still unknown. Some extrachromosomal plasmids and phages are also present in various H. pylori strains. Genetic exchange among plasmids and chromosomes, and involved DNA mobilization events, could explain part of H. pylori's genetic diversity. Here, we review our knowledge about the possible DNA transfer mechanisms in H. pylori and its implications in bacterial adaptation to the host environment.

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A Global Overview of the Genetic and Functional Diversity in the Helicobacter pylori cag Pathogenicity Island

Cited by 199 publications

References 61 publications

Worldwide Population Structure, Long-Term Demography, and Local Adaptation of Helicobacter pylori

Worldwide Population Structure, Long-Term Demography, and Local Adaptation of Helicobacter pylori

Functional Cytotoxin Associated Gene A in Helicobacter pylori Strains and Its Association with Integrity of Cag-pathogenicity Island and Histopathological Changes of Gastric Tissue

DNA transfer in the gastric pathogen Helicobacter pylori

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