Phase-variable restriction/modification systems are required for Helicobacter pylori colonization

Gauntlett, Jonathan C.; Nilsson, Hans‐Olof; Fulurija, Alma; Marshall, Barry J.; Benghezal, Mohammed

doi:10.1186/s13099-014-0035-z

Cited by 26 publications

(35 citation statements)

References 19 publications

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“…However, in contrast to the ModH5 phasevarion, flgE is positively regulated by the ModH1 OFF-phase. In line with these observations of ModH-mediated gene regulation, a role for ModH phase switching in H. pylori colonization has been implicated by the findings of a recent mouse model study 20 . Despite the predictive transcriptional evidence, the phenotypic role of ModH phase switching in H. pylori motility had not been examined.…”

Section: Introductionmentioning

confidence: 62%

Methylomic and phenotypic analysis of the ModH5 phasevarion of Helicobacter pylori

Srikhanta

Gorrell

Power

et al. 2017

Sci Rep

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The Helicobacter pylori phase variable gene modH, typified by gene HP1522 in strain 26695, encodes a N6-adenosine type III DNA methyltransferase. Our previous studies identified multiple strain-specific modH variants (modH1 – modH19) and showed that phase variation of modH5 in H. pylori P12 influenced expression of motility-associated genes and outer membrane protein gene hopG. However, the ModH5 DNA recognition motif and the mechanism by which ModH5 controls gene expression were unknown. Here, using comparative single molecule real-time sequencing, we identify the DNA site methylated by ModH5 as 5′-Gm6ACC-3′. This motif is vastly underrepresented in H. pylori genomes, but overrepresented in a number of virulence genes, including motility-associated genes, and outer membrane protein genes. Motility and the number of flagella of H. pylori P12 wild-type were significantly higher than that of isogenic modH5 OFF or ΔmodH5 mutants, indicating that phase variable switching of modH5 expression plays a role in regulating H. pylori motility phenotypes. Using the flagellin A (flaA) gene as a model, we show that ModH5 modulates flaA promoter activity in a GACC methylation-dependent manner. These findings provide novel insights into the role of ModH5 in gene regulation and how it mediates epigenetic regulation of H. pylori motility.

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Section: Introductionmentioning

confidence: 62%

Methylomic and phenotypic analysis of the ModH5 phasevarion of Helicobacter pylori

Srikhanta

Gorrell

Power

et al. 2017

Sci Rep

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“…Molecular investigations of phase-variable R-M genes have also been carried out on the Hp strain OND79, confirming their presence in six out of nine of the mentioned Hp strains, and further functional analyses were conducted. All three types of R-M system genes were reported to be equally distributed in the studied strain, while the functional analysis showed that the mod gene is a main player in colonization and in the regulation of different gene expressions ( 17 ).…”

Section: Discussionmentioning

confidence: 99%

PCR Based Detection of Phase Variable Genes in Pakistani Based Clinical Helicobacter pylori Strains

Ahmad

Rahman

et al. 2016

Jundishapur J Microbiol

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BackgroundThe distribution pattern of phase-variable genes varies from strain to strain and from region to region. The present study was carried out to investigate the distribution pattern of phase-variable genes within Pakistan-based Helicobacter pylori strains and to analyze and compare them with strains prevalent in other parts of the world.ObjectivesTo determine the distribution pattern of phase-variable genes in H. pylori strains circulating in Pakistan.Patients and MethodsBiopsy samples were collected from 85 symptomatic patients suffering from various upper gastrointestinal tract symptoms. The biopsy specimens were chopped, then inoculated on H. pylori-specific media and incubated in a Campylobacter Gas Generating kit. Positive isolates were further confirmed via staining and biochemical procedures. Primers were designed for five phase-variable genes using OligoCalc, an oligonucleotide properties calculator (version 3.26) according to parameters stipulated in the literature. Polymerase chain reaction (PCR) was performed on all positive isolates to determine the presence or absence of phase-variable genes.ResultsOn culturing, the prevalence of H. pylori infections in the samples was 44.7%. The prevalence was higher in females than in males, and it increased with age. PCR amplification revealed that the hsdR gene was present in 79% of samples, while the mod and β-subunit genes were present in 16% and 30% of samples, respectively. The streptococcal M protein gene was found in 79%, while the fliP gene was prevalent in 56%.ConclusionsThe distribution patterns of phase-variable genes in Pakistani H. pylori strains were found to be somewhat different. The dominant prevalence of the hsdR gene was an interesting finding, considering its role in bacterial defense in both micro- and macroenvironments.

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“…Although we have focused on inversion, improvements in targeted methylation analysis (59) could enable the study of cisacting sites at the P-and S-pilus promoters (49). Furthermore, PacBio sequencing can detect transposition, short sequence repeats, and slipped-strand mispairing; these capabilities may be useful for studying phase variation of other nonplus structures, such as flagella and lipoproteins (49), or restriction-modification systems, which impact phage defense and global gene expression (60)(61)(62). Additionally, with appropriate screen design, unbiased discovery of trans-acting factors for phase variation may be feasible.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive mutagenesis of thefimSpromoter regulatory switch reveals novel regulation of type 1 pili in uropathogenicEscherichia coli

Zhang

Susanto

Wan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Type 1 pili (T1P) are major virulence factors for uropathogenic Escherichia coli (UPEC), which cause both acute and recurrent urinary tract infections. T1P expression therefore is of direct relevance for disease. T1P are phase variable (both piliated and nonpiliated bacteria exist in a clonal population) and are controlled by an invertible DNA switch (fimS), which contains the promoter for the fim operon encoding T1P. Inversion of fimS is stochastic but may be biased by environmental conditions and other signals that ultimately converge at fimS itself. Previous studies of fimS sequences important for T1P phase variation have focused on laboratory-adapted E. coli strains and have been limited in the number of mutations or by alteration of the fimS genomic context. We surmounted these limitations by using saturating genomic mutagenesis of fimS coupled with accurate sequencing to detect both mutations and phase status simultaneously. In addition to the sequences known to be important for biasing fimS inversion, our method also identifies a previously unknown pair of 5′ UTR inverted repeats that act by altering the relative fimA levels to control phase variation. Thus we have uncovered an additional layer of T1P regulation potentially impacting virulence and the coordinate expression of multiple pilus systems.urinary tract infection | fimS | type 1 pili | phase variation | saturating chromosomal mutagenesis U rinary tract infections (UTIs) are common infections that mostly affect women with an annual cost of billions of dollars (1). They are caused mainly by uropathogenic Escherichia coli (UPEC), which rely on several virulence factors to cause disease (2); type 1 pili (T1P) are perhaps the most important of these (3). T1P present a tip adhesin, FimH, that binds specifically to mannose, which is found on several glycosylated surface proteins, such as uroplakins and α1-and β3-integrins (4, 5), in the mammalian bladder. Binding to mannosylated proteins initiates a cascade of events including UPEC invasion of host tissues (2), formation of intracellular structures (6), and activation of the host immune response (7). The interplay among these events determines the outcome of infection (8), ranging from full clearance to chronic active cystitis. T1P are important for most of these UTI stages and demonstrate dynamic regulation of expression that can be seen directly in human infections and urine (9, 10).Thus, understanding T1P regulation is fundamental to understanding UTI. T1P have been well studied (11), mostly in laboratory-adapted E. coli strains. T1P are encoded by the fim operon; their expression is phase variable via inversion of fimS, a chromosomal DNA segment containing the fim promoter (12). This binary epigenetic switch results in bacteria switching between fimbriated and nonfimbriated states. Inversion is mediated by the FimB and FimE recombinases, whose genes are located immediately upstream of fimS (13) and are found in most E. coli strains (14). Inversion is influenced by numerous signals, such as temperatu...

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Phase-variable restriction/modification systems are required for Helicobacter pylori colonization

Cited by 26 publications

References 19 publications

Methylomic and phenotypic analysis of the ModH5 phasevarion of Helicobacter pylori

Methylomic and phenotypic analysis of the ModH5 phasevarion of Helicobacter pylori

PCR Based Detection of Phase Variable Genes in Pakistani Based Clinical Helicobacter pylori Strains

Comprehensive mutagenesis of thefimSpromoter regulatory switch reveals novel regulation of type 1 pili in uropathogenicEscherichia coli

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