Skip to main content
Article thumbnail
Location of Repository

Phasevarions Mediate Random Switching of Gene Expression in Pathogenic Neisseria

By Yogitha N. Srikhanta, Stefanie J. Dowideit, Jennifer L. Edwards, Megan L. Falsetta, Hsing-Ju Wu, Odile B. Harrison, Kate L. Fox, Kate L. Seib, Tina L. Maguire, Andrew H.-J. Wang, Martin C. Maiden, Sean M. Grimmond, Michael A. Apicella and Michael P. Jennings


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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles


    1. (1984). Alteration of apparent restriction endonuclease recognition specificities by DNA methylases.
    2. (1999). An essential role for DNA adenine methylation in bacterial virulence.
    3. (1972). Assay of b-galactosidase.
    4. (2005). Biofilm Formation by Neisseria gonorrhoeae.
    5. (2002). Biofilms, antimicrobial resistance, and airway infection.
    6. (1999). Characterization of a CACAG pentanucleotide repeat in Pasteurella haemolytica and its possible role in modulation of a novel type III restriction-modification system.
    7. (2007). Characterization of the OxyR regulon of Neisseria gonorrhoeae.
    8. (2002). Complex restriction enzymes: NTP-driven molecular motors.
    9. (2004). Dam inactivation in Neisseria meningitidis: Prevalence among diverse hyperinvasive lineages.
    10. (1995). Differential binding of Lrp to two sets of pap DNA binding sites mediated by Pap I regulates Pap phase variation in Escherichia coli.
    11. (2004). Distribution of surface protein variants among hyperinvasive meningococci: Implications for vaccine design.
    12. (2001). DNA adenine methylase is essential for viability and plays a role in the pathogenesis of Yersinia pseudotuberculosis and Vibrio cholerae.
    13. (1999). DNA adenine methylase mutants of Salmonella typhimurium show defects in protein secretion, cell invasion, and M cell cytotoxicity.
    14. (2000). DNA methylation-dependent regulation of pef expression in Salmonella typhimurium.
    15. (1971). DNA restrictions and modification mechanisms in bacteria.
    16. (1991). Endonuclease (R) subunits of type-I and type-III restriction-modification enzymes contain a helicase-like domain.
    17. (2006). Epigenetic gene regulation in the bacterial world.
    18. (1998). Functional analysis of conserved motifs in type III restriction-modification enzymes.
    19. (1988). gene and some EcoP1 mod mutants.
    20. (2002). Gene expression profile in Neisseria meningitidis and Neisseria lactamica upon host-cell contact: From basic research to vaccine development.
    21. (1999). Gonococcal infections in adults.
    22. (2007). Haemophilus influenzae phasevarions have evolved from type III DNA restriction systems into epigenetic regulators of gene expression.
    23. (2006). High allelic diversity in the methyltransferase gene of a phase variable type III restriction-modification system has implications for the fitness of Haemophilus influenzae.
    24. (2003). Identification of a cell envelope protein (MtrF) involved in hydrophobic antimicrobial resistance in Neisseria gonorrhoeae.
    25. (2003). Identification of iron-activated and -repressed Fur-dependent genes by transcriptome analysis of Neisseria meningitidis group B.
    26. (2005). Identification of the iron-responsive genes of Neisseria gonorrhoeae by microarray analysis in defined medium.
    27. (2004). Inactivation of deoxyadenosine methyltransferase (dam) attenuates Haemophilus influenzae virulence.
    28. (2007). Inference of bacterial microevolution using multilocus sequence data.
    29. (1994). Interaction of EcoP15I DNA methyltransferase with oligonucleotides containing the asymmetric sequence 59-CAGCAG-39.
    30. (2007). MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) software version 4.0.
    31. (1988). Methionine biosynthesis in Enterobacteriaceae: Biochemical, regulatory, and evolutionary aspects.
    32. (1979). Methylation and cleavage sequences of the EcoP1 restriction-modification enzyme.
    33. (1997). Microbial genetics. The tinkerer’s evolving toolbox.
    34. (1998). Modulation of Neisseria gonorrhoeae susceptibility to vertebrate antibacterial peptides due to a member of the resistance/nodulation/division efflux pump family.
    35. (1998). Molecular characterization of LbpB, the second lactoferrin-binding protein of Neisseria meningitidis.
    36. (1993). Molecular characterization of the 98-kilodalton iron-regulated outer membrane protein of Neisseria meningitidis.
    37. (1989). Molecular cloning: A laboratory manual. 2 nd edition.
    38. (1998). Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms.
    39. (2006). N6-methyl-adenine: An epigenetic signal for DNAprotein interactions.
    40. (2006). Neisseria gonorrhoeae DNA recombination and repair enzymes protect against oxidative damage caused by hydrogen peroxide.
    41. (2000). Neisseria gonorrhoeae elicits membrane ruffling and cytoskeletal rearrangements upon infection of primary human endocervical and ectocervical cells.
    42. (2005). Oral immunization with a dam mutant of Yersinia pseudotuberculosis protects against plague.
    43. (2004). Oxidative stress inactivates cobalaminindependent methionine synthase (MetE) in Escherichia coli. PLoS Biol 2: e336.
    44. (2006). PerR controls Mn-dependent resistance to oxidative stress in Neisseria gonorrhoeae.M o l
    45. (2002). Phase variable restriction-modification systems in Moraxella catarrhalis.
    46. (2007). Phase variable type III restrictionmodification systems of host-adapted bacterial pathogens.
    47. (2000). Phase variation of Ag43 in Escherichia coli: Dam-dependent methylation abrogates OxyR binding and OxyR-mediated repression of transcription.
    48. (2000). Quantification of biofilm structures by the novel computer program COMSTAT.
    49. (1996). Questions about gonococcal pilus phase- and antigenic variation.
    50. (2000). REBASE—Restriction enzymes and methylases.
    51. (1997). Recognition and cleavage of DNA by type-II restriction endonucleases.
    52. (2005). Regulation of mtrF expression in Neisseria gonorrhoeae and its role in high-level antimicrobial resistance.
    53. (2000). Regulation of Pap phase variation. Lrp is sufficient for the establishment of the phase off pap DNA methylation pattern and repression of pap transcription in vitro.
    54. (1990). Regulation of pap pilin phase variation by a mechanism involving differential dam methylation states.
    55. (2000). Repeatassociated phase variable genes in the complete genome sequence of Neisseria meningitidis strain MC58.
    56. (2000). Role of biofilms in antimicrobial resistance.
    57. (2002). Roles of the recJ and recN genes in homologous recombination and DNA repair pathways of Neisseria gonorrhoeae.
    58. (2001). Salmonella DNA adenine methylase mutants confer cross-protective immunity.
    59. (1998). Short-sequence DNA repeats in prokaryotic genomes.
    60. (1995). Structure-guided analysis reveals nine sequence motifs conserved among DNA amino-methyltransferases, and suggests a catalytic mechanism for these enzymes.
    61. (2000). The length of a tetranucleotide repeat tract in Haemophilus influenzae determines the phase variation rate of a gene with homology to type III DNA methyltransferases.
    62. (2007). The phase variable allele of the pili glycosylation gene pglA (pgtA) is not strongly associated with strains of Neisseria gonorrhoeae isolated from patients with disseminated gonococcal infection.
    63. (2005). The phasevarion: A genetic system controlling coordinated, random switching of expression of multiple genes.
    64. (1996). The Staden sequence analysis package.
    65. (1980). Tomasz A
    66. (2002). Transcriptional phase variation of a type III restriction-modification system in Helicobacter pylori.
    67. (1995). Type III restriction endonucleases translocate DNA in a reaction driven by recognition site-specific ATP hydrolysis.
    68. (2006). Vaccine potential of the Neisseria meningitidis lactoferrin-binding proteins LbpA and LbpB.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.