Suker, Janet; (1997) Variation of meningococcal porin antigens. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The aim of this thesis was to investigate molecular variation among porin proteins between and within species of Neisseria. Emphasis was placed on the meningococcal PorA protein because of its use as an epidemiological marker and component of novel meningococcal vaccines. Nucleotide sequences were determined for genes encoding PorA from representative strains of N. meningitidis and porin classes from four Neisseria species (N. lactamica, N. sicca, N. flavescens and N. polysaccharea). These data facilitated: (i) determination of the secondary structures of these proteins; (ii) localisation of potential epitopes in previously non-serosubtypable strains; (iii) phylogenetic analyses of relationships between variants of these genes between and within species; and (iv) elucidation of mechanisms of genetic exchange between the Neisseria. All Neisseria porins examined shared a common secondary structure which was consistent with the model proposed for the secondary structure of meningococcal porins. It was suggested that species of Neisseria share a common gene pool which is a potential source of diversity via the processes of horizontal genetic exchange. PorA was the most divergent porin and was proposed to have a unique, possibly immunological, role related to antigenic variation within surface loops, VR1 and VR2. Analysis of sequence diversity among 55 representative serogroup A meningococci revealed four porA 'gene types' that correlated with subgroup designations and epidemiology. A new scheme was proposed for the reassignment of PorA subtype based on the amino acid sequences of VR1 and VR2 rather than serology. Minor variants of PorA were identified which were serologically indistinguishable but considered to be members of the same VR family under the new scheme. The antigenic importance of such sequence variation was investigated in the P1.10 VR family. It was found that small changes in epitope sequence result in major antigenic differences in PorA. Antigenic variation in PorA has implications for the design and assessment of meningococcal vaccines, but analysis of such variation increases our understanding of the population biology of N. meningitidis.

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