Phase Variation Mediates Reductions in Expression of Surface Proteins during Persistent Meningococcal Carriage

Alamro, Mohamed; Bidmos, Fadil A.; Chan, Hannah; Oldfield, Neil J.; Newton, Emma; Bai, Xilian; Aidley, Jack; Care, Rory; Mattick, C; Turner, David P. J.; Neal, Keith; Ala’Aldeen, Dlawer A. A.; Feavers, Ian M.; Borrow, Ray; Bayliss, Christopher D.

doi:10.1128/iai.01521-14

Cited by 40 publications

(66 citation statements)

References 49 publications

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“…The mutations in the SSRs of fetA (which encodes an iron-regulated ferric enterochelin receptor, [67]) and modA12 (coding for a phase-variable type III methyltransferase, [68]) are not expected to result in expression differences between the respective throat and blood isolates as indicated by available data [68, 69]. Changes in the SSR tract length in pilC1 , however, lead to the generation of a truncated Tfp tip protein PilC1.…”

Section: Resultsmentioning

confidence: 99%

“…With respect to the hypothesis that the genetic variation observed in the paired strain samples results from WHE, Bayliss and co-workers showed that mutants at SSR loci are indeed randomly generated in the nasopharynx during colonization [69]. By analyzing mononucleotide repeat tracts at meningococcal SSR loci during carriage they further estimated that the switching rate at contingency loci with mononucleotide repeat tracts is about 0.06 mutations/gene/month of carriage [69].…”

Section: Discussionmentioning

confidence: 99%

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Comparative Genome Sequencing Reveals Within-Host Genetic Changes in Neisseria meningitidis during Invasive Disease

et al. 2017

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Some members of the physiological human microbiome occasionally cause life-threatening disease even in immunocompetent individuals. A prime example of such a commensal pathogen is Neisseria meningitidis, which normally resides in the human nasopharynx but is also a leading cause of sepsis and epidemic meningitis. Using N. meningitidis as model organism, we tested the hypothesis that virulence of commensal pathogens is a consequence of within host evolution and selection of invasive variants due to mutations at contingency genes, a mechanism called phase variation. In line with the hypothesis that phase variation evolved as an adaptation to colonize diverse hosts, computational comparisons of all 27 to date completely sequenced and annotated meningococcal genomes retrieved from public databases showed that contingency genes are indeed enriched for genes involved in host interactions. To assess within-host genetic changes in meningococci, we further used ultra-deep whole-genome sequencing of throat-blood strain pairs isolated from four patients suffering from invasive meningococcal disease. We detected up to three mutations per strain pair, affecting predominantly contingency genes involved in type IV pilus biogenesis. However, there was not a single (set) of mutation(s) that could invariably be found in all four pairs of strains. Phenotypic assays further showed that these genetic changes were generally not associated with increased serum resistance, higher fitness in human blood ex vivo or differences in the interaction with human epithelial and endothelial cells in vitro. In conclusion, we hypothesize that virulence of meningococci results from accidental emergence of invasive variants during carriage and without within host evolution of invasive phenotypes during disease progression in vivo.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparative Genome Sequencing Reveals Within-Host Genetic Changes in Neisseria meningitidis during Invasive Disease

et al. 2017

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“…In bacteria, VNTRs have been implicated in the ON/OFF switching of phase variable genes in Neisseria [123,124]. In mycobacteria, intragenic VNTR loci variation has been shown to modify the structure and function of the proteins affected [125].…”

Section: The Consequences Of Genomic Diversity In Mtbcmentioning

confidence: 99%

Consequences of genomic diversity in Mycobacterium tuberculosis

Coscollá

Gagneux

2014

Seminars in Immunology

389

370

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The causative agent of human tuberculosis, Mycobacterium tuberculosis complex (MTBC), comprises seven phylogenetically distinct lineages associated with different geographical regions. Here we review the latest findings on the nature and amount of genomic diversity within and between MTBC lineages. We then review recent evidence for the effect of this genomic diversity on mycobacterial phenotypes measured experimentally and in clinical settings. We conclude that overall, the most geographically widespread Lineage 2 (includes Beijing) and Lineage 4 (also known as Euro-American) are more virulent than other lineages that are more geographically restricted. This increased virulence is associated with delayed or reduced pro-inflammatory host immune responses, greater severity of disease, and enhanced transmission. Future work should focus on the interaction between MTBC and human genetic diversity, as well as on the environmental factors that modulate these interactions.

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“…The single sequence repeats can cause on/off switches in gene expression when they are within the open reading frame, or modulation of expression when they are in the gene promoter. During colonisation of humans, it has recently been shown that OMPs at contingency loci that elicit an immune response become less expressed during persistent carriage (Alamro et al, 2014). This is key evidence that localised hypermutation has evolved to enable persistence in the nasopharynx.…”

Section: Adaptation To the Immune Responsementioning

confidence: 98%

“…The host also responds to sub-capsular antigens. One of the most effective mechanisms of evasion of the immune response is phase variation of surface-expressed proteins, and this has been shown to occur during persistent meningococcal carriage (Alamro et al, 2014). Phase variation is a result of high-frequency mutation and recombination rates within specific loci (contingency loci) prior to a selective pressure (such as the presence of antibody within the nasopharynx).…”

Section: Adaptation To the Immune Responsementioning

confidence: 99%