Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.647100
Title: Investigation of the determinants and biological consequences of phase variation of the fetA gene of Neisseria meningitides
Author: Alamro, Mohamed Saleh
ISNI:       0000 0004 5365 194X
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2015
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Abstract:
Neisseria meningitidis (Nm) is an opportunistic pathogen that asymptomatically colonises the human upper respiratory tract (nasopharynx) in a state known as carriage. Antigenic or phase variation (PV) of outer membrane proteins (OMP) contributes to adaptability of Nm during carriage. PV of five Nm OMPs was investigated in multiple isolates from 21 carriers persistently colonised with a single strain. PV of these genes was mediated by simple sequence repeats (SSRs). Changes in SSRs were detected using GeneScan assays and correlated with expression states by Western blotting. Mutations in SSR loci occurred at a rate of 0.07 mutations/gene/month. These mutations caused reductions in gene expression of fetA and combinations of OMPs during persistent carriage. Levels of anti-FetA IgG-antibodies were measured in the sera of the 21 carriers using multiplex immunoassays containing four allelic-variant FetA proteins coupled to fluorescent microspheres. High levels of FetA-antibodies were detected in multiple carrier sera with some allele-specific reactivity. Evidence was found for reductions in FetA expression to be associated with escape of anti-FetA IgG antibodies. The fetA gene exhibited a high in vitro PV frequency of 3.9 X 10-3 for switching from an 8C to 9C tract. In addition to PV-mediated expression and fur regulation, a putative binding site for a second regulator of fetA gene expression was detected 451 bp upstream of the fetA core promoter. Utilisation of ferric-enterobactin via FetA was limited to serogroup B strains as neither serogroup Y nor E strains exhibited an ability to utilise ferric-enterobactin as the sole iron source. Utilisation of siderophores-produced by four other bacterial species was not detected. In summary, this study shows that PV-mediated reductions in gene expression occur during long-term meningococcal carriage. These reductions in gene expression are posited to be driven by an active immune response and thus PV mediates immune escape of Nm in vivo.
Supervisor: Bayliss, Christopher Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.647100  DOI: Not available
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