Regulation of Pap Phase Variation

Weyand, Nathan J.; Low, David A.

doi:10.1074/jbc.275.5.3192

Cited by 44 publications

(7 citation statements)

References 41 publications

(39 reference statements)

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“…The pap pili-mediating adhesion of UPEC to mammalian uroepithelial cells is epigenetically regulated through methylation at the intergenic region of pap IB to produce “ON/OFF” phase variation (expression or non-expression, respectively) by individual cells ( 30 , 34 , 38 , 41 ). The phase variation mechanism via Dam methylation pattern acts a switch for the expression of the operon and confirms reports for the significance of Lrp, PapI, and Dam as transcription regulators ( 28 , 31 , 34 , 38 , 42 , 43 ). The reversible expression of pap is theorized to allow the bacteria to attach and detach from the urogenital tissues, which in turn enables colonization and infection ( 33 ).…”

Section: Introductionsupporting

confidence: 86%

Epigenetic Influence of Dam Methylation on Gene Expression and Attachment in Uropathogenic Escherichia coli

Stephenson¹,

Brown²

2016

Front. Public Health

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Urinary tract infections (UTI) are among the most frequently encountered infections in clinical practice globally. Predominantly a burden among female adults and infants, UTIs primarily caused by uropathogenic Escherichia coli (UPEC) results in high morbidity and fiscal health strains. During pathogenesis, colonization of the urinary tract via fimbrial adhesion to mucosal cells is the most critical point in infection and has been linked to DNA methylation. Furthermore, with continuous exposure to antibiotics as the standard therapeutic strategy, UPEC has evolved to become highly adaptable in circumventing the effect of antimicrobial agents and host defenses. Hence, the need for alternative treatment strategies arises. Since differential DNA methylation is observed as a critical precursor to virulence in various pathogenic bacteria, this body of work sought to assess the influence of the DNA adenine methylase (dam) gene on gene expression and cellular adhesion in UPEC and its potential as a therapeutic target. To monitor the influence of dam on attachment and FQ resistance, selected UPEC dam mutants created via one-step allelic exchange were transformed with cloned qnrA and dam complement plasmid for comparative analysis of growth rate, antimicrobial susceptibility, biofilm formation, gene expression, and mammalian cell attachment. The absence of DNA methylation among dam mutants was apparent. Varying deficiencies in cell growth, antimicrobial resistance and biofilm formation, alongside low-level increases in gene expression (recA and papI), and adherence to HEK-293 and HTB-9 mammalian cells were also detected as a factor of SOS induction to result in increased mutability. Phenotypic characteristics of parental strains were restored in dam complement strains. Dam’s vital role in DNA methylation and gene expression in local UPEC isolates was confirmed. Similarly to dam-deficient Enterohemorrhagic E. coli (EHEC), these findings suggest unsuccessful therapeutic use of Dam inhibitors against UPEC or dam-deficient UPEC strains as attenuated live vaccines. However, further investigations are necessary to determine the post-transcriptional influence of dam on the regulatory network of virulence genes central to pathogenesis.

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Section: Introductionsupporting

confidence: 86%

Epigenetic Influence of Dam Methylation on Gene Expression and Attachment in Uropathogenic Escherichia coli

Stephenson¹,

Brown²

2016

Front. Public Health

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“…In these studies the mechanisms of attenuation (genes regulated) are unknown. In contrast, there are a few well-established examples of Dam mediated phase variation of genes encoding individual virulence factors[47]–[49], for example the pyelonephritis-associated pilus ( pap ) operon in uropathogenic Escherichia coli [47],[50],[51]. The fundamental characteristic of these DNA-methylation-dependent phase variable systems is that the target site's methylation state affects the DNA binding of a regulatory protein, which directly regulates transcription.…”

Section: Discussionmentioning

confidence: 99%

Phasevarions Mediate Random Switching of Gene Expression in Pathogenic Neisseria

et al. 2009

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Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, the random switching of the modA gene controls expression of a phase-variable regulon of genes (a “phasevarion”), via differential methylation of the genome in the modA ON and OFF states. Phase-variable mod genes are also present in Neisseria meningitidis and Neisseria gonorrhoeae, suggesting that phasevarions may occur in these important human pathogens. Phylogenetic studies on phase-variable mod genes associated with type III restriction modification (R-M) systems revealed that these organisms have two distinct mod genes—modA and modB. There are also distinct alleles of modA (abundant: modA11, 12, 13; minor: modA4, 15, 18) and modB (modB1, 2). These alleles differ only in their DNA recognition domain. ModA11 was only found in N. meningitidis and modA13 only in N. gonorrhoeae. The recognition site for the modA13 methyltransferase in N. gonorrhoeae strain FA1090 was identified as 5′-AGAAA-3′. Mutant strains lacking the modA11, 12 or 13 genes were made in N. meningitidis and N. gonorrhoeae and their phenotype analyzed in comparison to a corresponding mod ON wild-type strain. Microarray analysis revealed that in all three modA alleles multiple genes were either upregulated or downregulated, some of which were virulence-associated. For example, in N. meningitidis MC58 (modA11), differentially expressed genes included those encoding the candidate vaccine antigens lactoferrin binding proteins A and B. Functional studies using N. gonorrhoeae FA1090 and the clinical isolate O1G1370 confirmed that modA13 ON and OFF strains have distinct phenotypes in antimicrobial resistance, in a primary human cervical epithelial cell model of infection, and in biofilm formation. This study, in conjunction with our previous work in H. influenzae, indicates that phasevarions may be a common strategy used by host-adapted bacterial pathogens to randomly switch between “differentiated” cell types.

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“…DNA replication generates a hemimethylated GATC distal site; methylation of the GATC proximal site and increased levels of PapI result in Lrp binding to the GATC distal site. These events allow the expression of pili, thus giving rise to uropathogenic E. coli (Weyand and Low ; Low et al . ).…”

Section: Gene Regulation and Virulencementioning

confidence: 99%

Bacteriophage adenine methyltransferase: a life cycle regulator? Modelled usingVibrio harveyimyovirus like

2012

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Summary The adenine methyltransferase (DAM) gene methylates GATC sequences that have been demonstrated in various bacteria to be a powerful gene regulator functioning as an epigenetic switch, particularly with virulence gene regulation. However, overproduction of DAM can lead to mutations, giving rise to variability that may be important for adaptation to environmental change. While most bacterial hosts carry a DAM gene, not all bacteriophage carry this gene. Currently, there is no literature regarding the role DAM plays in life cycle regulation of bacteriophage. Vibrio campbellii strain 642 carries the bacteriophage Vibrio harveyi myovirus like (VHML) that has been proven to increase virulence. The complete genome sequence of VHML bacteriophage revealed a putative adenine methyltransferase gene. Using VHML, a new model of phage life cycle regulation, where DAM plays a central role between the lysogenic and lytic states, will be hypothesized. In short, DAM methylates the rha antirepressor gene and once methylation is removed, homologous CI repressor protein becomes repressed and non‐functional leading to the switching to the lytic cycle. Greater understanding of life cycle regulation at the genetic level can, in the future, lead to the genesis of chimeric bacteriophage with greater control over their life cycle for their safe use as probiotics within the aquaculture industry.

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Regulation of Pap Phase Variation

Abstract: The pyelonephritis-associated pili (pap) operon in

Cited by 44 publications

References 41 publications

Epigenetic Influence of Dam Methylation on Gene Expression and Attachment in Uropathogenic Escherichia coli

Epigenetic Influence of Dam Methylation on Gene Expression and Attachment in Uropathogenic Escherichia coli

Phasevarions Mediate Random Switching of Gene Expression in Pathogenic Neisseria

Bacteriophage adenine methyltransferase: a life cycle regulator? Modelled usingVibrio harveyimyovirus like

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