Phasevarions mediate random switching of gene expression in pathogenic Neisseria.

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 reg...

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Autores principales: 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, Michael P Jennings
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Publicado: Public Library of Science (PLoS) 2009
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spelling oai:doaj.org-article:08072cebc5074ae19882428ccdcc5b0b2021-12-02T19:59:47ZPhasevarions mediate random switching of gene expression in pathogenic Neisseria.1553-73661553-737410.1371/journal.ppat.1000400https://doaj.org/article/08072cebc5074ae19882428ccdcc5b0b2009-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19390608/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Many 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.Yogitha N SrikhantaStefanie J DowideitJennifer L EdwardsMegan L FalsettaHsing-Ju WuOdile B HarrisonKate L FoxKate L SeibTina L MaguireAndrew H-J WangMartin C MaidenSean M GrimmondMichael A ApicellaMichael P JenningsPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 4, p e1000400 (2009)
institution DOAJ
collection DOAJ
language EN
topic Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
spellingShingle Immunologic diseases. Allergy
RC581-607
Biology (General)
QH301-705.5
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
Michael P Jennings
Phasevarions mediate random switching of gene expression in pathogenic Neisseria.
description 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.
format article
author 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
Michael P Jennings
author_facet 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
Michael P Jennings
author_sort Yogitha N Srikhanta
title Phasevarions mediate random switching of gene expression in pathogenic Neisseria.
title_short Phasevarions mediate random switching of gene expression in pathogenic Neisseria.
title_full Phasevarions mediate random switching of gene expression in pathogenic Neisseria.
title_fullStr Phasevarions mediate random switching of gene expression in pathogenic Neisseria.
title_full_unstemmed Phasevarions mediate random switching of gene expression in pathogenic Neisseria.
title_sort phasevarions mediate random switching of gene expression in pathogenic neisseria.
publisher Public Library of Science (PLoS)
publishDate 2009
url https://doaj.org/article/08072cebc5074ae19882428ccdcc5b0b
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