title: Phase variation mediates reductions in expression of surface proteins during persistent meningococcal carriage.
abstract: Asymptomatic and persistent colonization of the upper respiratory tract by Neisseria meningitidis occurs despite elicitation of adaptive immune responses against surface antigens. A putative mechanism for facilitating host persistence of this bacterial commensal and pathogen is alterations in expression of surface antigens by simple sequence repeat (SSR)-mediated phase variation. We investigated how often phase variation occurs during persistent carriage by analyzing the SSRs of eight loci in multiple isolates from 21 carriers representative of 1 to 6 months carriage. Alterations in repeat number were detected by a GeneScan analysis and occurred at 0.06 mutations/gene/month of carriage. The expression states were determined by Western blotting and two genes, fetA and nadA, exhibited trends toward low expression states. A critical finding from our unique examination of combinatorial expression states, "phasotypes," was for significant reductions in expression of multiple phase-variable surface proteins during persistent carriage of some strains. The immune responses in these carriers were examined by measuring variant-specific PorA IgG antibodies, capsular group Y IgG antibodies and serum bactericidal activity in concomitant serum samples. Persistent carriage was associated with high levels of specific IgG antibodies and serum bactericidal activity while recent strain acquisition correlated with a significant induction of antibodies. We conclude that phase-variable genes are driven into lower expression states during long-term persistent meningococcal carriage, in part due to continuous exposure to antibody-mediated selection, suggesting localized hypermutation has evolved to facilitate host persistence.
authors.affiliation: Department of Genetics, University of Leicester, Leicester, United Kingdom.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Alamro
authors.forename: Fadil A
authors.initials: FA
authors.lastname: Bidmos
authors.forename: Hannah
authors.initials: H
authors.lastname: Chan
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Oldfield
authors.forename: Emma
authors.initials: E
authors.lastname: Newton
authors.forename: Xilian
authors.initials: X
authors.lastname: Bai
authors.forename: Jack
authors.initials: J
authors.lastname: Aidley
authors.forename: Rory
authors.initials: R
authors.lastname: Care
authors.forename: Claire
authors.initials: C
authors.lastname: Mattick
authors.forename: David P J
authors.initials: DP
authors.lastname: Turner
authors.forename: Keith R
authors.initials: KR
authors.lastname: Neal
authors.forename: Dlawer A A
authors.initials: DA
authors.lastname: Ala'aldeen
authors.forename: Ian
authors.initials: I
authors.lastname: Feavers
authors.forename: Ray
authors.initials: R
authors.lastname: Borrow
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Bayliss
mesh_terms: D056704:Adaptive Immunity / Q000502:physiology; D000907:Antibodies, Bacterial / Q000276:immunology; D000940:Antigenic Variation; D015153:Blotting, Western; D020869:Gene Expression Profiling; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D008565:Membrane Proteins / Q000276:immunology*; D008589:Meningococcal Infections / Q000235:genetics / Q000276:immunology*; D018895:Microsatellite Repeats; D009345:Neisseria meningitidis / Q000235:genetics / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000907:Antibodies, Bacterial; D007074:Immunoglobulin G; D008565:Membrane Proteins