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Potentiation of phase variation in multiple outer membrane proteins during spread of the hyperinvasive Neisseria meningitidis serogroup W ST-11 lineage.

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posted on 03.06.2019, 13:37 by LR Green, N Dave, AB Adewoye, J Lucidarme, SA Clark, NJ Oldfield, DPJ Turner, R Borrow, CD Bayliss
BACKGROUND: Since 2009, increases in invasive meningococcal disease have occurred in the United Kingdom due to a sub-lineage of the Neisseria meningitidis serogroup W ST-11 clonal complex (the 'original-UK' strain). In 2013, a descendent sub-strain (the '2013-strain') became the dominant disease-causing variant. Multiple outer membrane proteins (OMP) of meningococci are subject to phase-variable switches in expression due to hypermutable simple sequence repeats (SSR). We investigated whether alterations in phase-variable genes may have impacted on the relative prevalence of the original-UK and 2013 sub-strains using multiple disease and carriage isolates. METHODS: Repeat numbers were determined by either bioinformatic analysis of whole-genome sequencing data or PCR-amplification and sizing of fragments from genomic DNA extracts. Immunoblotting or sequence-translation identified expression states. RESULTS: Significant increases in repeat number were detected between the original-UK and 2013-strains in genes encoding PorA, NadA and two Opa variants. Invasive and carriage isolates exhibited similar repeat numbers but the absence of pilC gene expression was frequently associated with disease. CONCLUSIONS: Elevated repeat numbers in OMP genes of the 2013-strain are indicative of higher phase variation rates suggesting that rapid expansion of this strain was due to a heightened ability to evade host immune responses during transmission and asymptomatic carriage.


This project was supported by the Medical Research Council [MR/M020193/1]. The PilC monoclonal antibody was a kind gift of Christopher E. Thomas from the University of North Carolina at Chapel Hill. This publication made use of the Meningitis Research Foundation Genome Library developed by Public Health England, the Wellcome Trust Sanger Institute and the University of Oxford, a project funded by Meningitis Research Foundation. This study also made use of the Neisseria Multi Locus Sequence Typing website (https://pubmlst.org/neisseria/) hosted by the University of Oxford and developed with funding from the Wellcome Trust and European Union.



Journal of Infectious Diseases, 2019

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/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Genetics and Genome Biology


AM (Accepted Manuscript)

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Journal of Infectious Diseases


Oxford University Press (OUP) for Infectious Diseases Society of America



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Supplementary materials include: Supplementary Table 1; Oligonucleotide sequences. Supplementary Table 2; Allele numbers for seven phase-variable scOMPs. Supplementary Table 3; Comparison of repeat numbers obtained by whole genome sequence analysis and GeneScan. Supplementary Table 4; Comparison of repeat numbers for invasive versus carriage isolates for both the MenW cc11 original-UK and 2013 -strains. Supplementary Fig. 1; Alignment of sequences flanking repetitive tracts. Supplementary Fig. 2; Repeat number distributions for fetA and nalP. Supplementary Fig. 3; Western and immunoblots with PorA and Opa antibodies to confirm the expression states of selected MenW ST-11 isolates. Supplementary Fig. 4; Comparison of expression states for multiple PV genes between MenW ST-11 carriage isolates and subsets of invasive isolates. Supplementary Data File 1; Excel spreadsheet listing all the isolates utilized with the repeat numbers and expression states for the phase-variable genes of each isolate.