Intragenic recombination leads to pilus antigenic variation in Neisseria gonorrhoeae

Hagblom, Per; Segal, E.; Billyard, E.; So, Magdalene

doi:10.1038/315156a0

Cited by 331 publications

(253 citation statements)

References 17 publications

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“…A variety of pathogens, including gonococci and trypanosomes, undergo antigenic variation by recombination with homologous sequences elsewhere on the chromosome (10,17). This mechanism was previously dismissed in the case of streptococcal M protein because of the singlecopy nature of emm6 (48).…”

Section: Discussionmentioning

confidence: 99%

Identification of a divergent M protein gene and an M protein-related gene family in Streptococcus pyogenes serotype 49

1989

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The antigenically variant M protein of Streptococcus pyogenes enhances virulence by promoting resistance to phagocytosis. The serum opacity factor (OF), produced by a subset of M serotypes, is also antigenically variant, and its antigenic variability exactly parallels that of M protein. OF-positive and OF-negative streptococci are also phenotypically distinguishable by a number of other criteria. In order to study the differences between OF-positive and OF-negative streptococci, we cloned and sequenced the type 49 M protein gene (emm49), the first to be cloned from an OF-positive strain. This gene showed evolutionary divergence from the OF-negative M protein genes studied previously. Furthermore, emm49 was part of a gene family, in contrast to the single-copy nature of previously characterized M protein genes.The M protein, a major virulence factor of Streptococcus pyogenes (group A streptococci), enhances the pathogenicity of the organism by blocking phagocytosis in the nonimmunized host (26,27). Antibodies to M protein develop in infected individuals and confer immunity (34). Streptococcal M protein, however, is antigenically variant, and opsonic antibodies to M protein are largely type specific. Thus, with 70 or more M protein serotypes (35), group A streptococci can successfully avoid immune surveillance.Molecular biological techniques have increased our knowledge of the structure of M protein and its antigenic variability. Five M protein genes have been cloned, and all have been at least partially sequenced (16,24,40,42,46). The M proteins encoded by these sequenced genes have a common framework which includes a conserved signal peptide, a hypervariable amino terminus, and a highly conserved C-terminus. Each gene also appears to contain some internal sequence repetitions, although the extent and degree of similarity of these repeats vary among the genes. Furthermore, regions preceding and following these M protein genes are conserved (16,42). This suggests that the genes are situated in a common expression site on the streptococcal chromosome.Our understanding of how the M protein hypervariable regions evolved is still incomplete. Duplication and deletion of intragenic repeats present in the variable regions of M molecules is a possible mechanism for the introduction of variant amino acids into the M protein sequences (25). Recent evidence shows that intragenic recombination can indeed introduce variant opsonic determinants into the repetitive regions of the M6 protein (28). Not all of the opsonic antigenic determinants of M proteins, however, are located in the repetitive regions of the molecules (25, 32). Thus, additional mechanisms must be involved in the generation of M protein antigenic diversity.A model explaining the generation of M protein antigenic diversity must account for the fact that other streptococcal proteins exhibit antigenic diversity in a nonrandom manner relative to the M type. Among these are the T antigen, a * Corresponding author. (18) and by genetic means (8). Clearly, the processe...

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Section: Discussionmentioning

confidence: 99%

Identification of a divergent M protein gene and an M protein-related gene family in Streptococcus pyogenes serotype 49

1989

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“…Gonococcal and meningococcal pili are characteristically subject, both in vivo and in vitro, to phase and antigenic variation caused by recombinational events that involve the insertion of alternative silent partial pilin (pilS) sequences into a pilin expression (pilE) locus (Haas & Meyer, 1986;Hagblom et al, 1985;Potts & Saunders, 1988;Segal et al, 1986;Seiffert et al, 1988). The presence of DNA sequences homologous to the entire structural gene for gonococcal pilin (pilE) appears to be limited to the pathogenic members of the genus Neisseria (Ah0 et al, 1987).…”

Section: Introductionmentioning

confidence: 99%

Identification of Epitopes Recognized by Monoclonal Antibodies SM1 and SM2 Which React with All Pili of Neisseria gonorrhoeae but Which Differentiate between Two Structural Classes of Pili Expressed by Neisseria meningitidis and the Distribution of Their Encoding Sequences in the Genomes of Neisseria spp.

Virji

Heckels²,

Potts³

et al. 1989

Microbiology

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The pili expressed by all isolates of Neisseria gonorrhoeae react with two monoclonal antibodies, SM1 and SM2. In contrast, although many isolates of Neisseria meningitidis also express pili (class I) which react with antibodies SM1 and SM2, a proportion express pili (class 11) which fail to react. In order to define the epitopes recognized by these antibodies, a series of overlapping peptides corresponding to the amino acid sequence of conserved regions of gonococcal pili have been synthesized. The minimum epitope recognized by antibody SM1 was found to comprise a linear peptide EYYLN, corresponding to residues 49-53 of mature pilin. In contrast, antibody SM2 reacted with a number of peptides from around the cysteine residue (Cys 1) at position 120, suggesting that an extended region may contribute to a conformational epitope recognized by this antibody in the native protein. The identification of the two epitopes defines structural differences between the classes of pili expessed by meningococci. In order to determine the distribution of pilin gene sequences in Neisseria we used as hybridization probes an oligonucleotide (PS 1) with the sequence 5'-GAGTATTACCTGAATCA-3' which spans the coding region for the SMl epitope, and a fragment of the 3' end of the gonococcal pilE gene which contains conserved sequences flanking the two Cys codons and encodes the SM2 epitope. All strains of N . gonorrhoeae and N. meningitidis tested, regardless of piliation phenotype, harboured DNA sequences homologous to those encoding the carboxy-terminus of meningococcal class I pilin. Furthermore, all gonococci and all meningocococci producing class I pili hybridized with oligonucleotide probe PS 1. Non-reverting non-piliated derivatives of previously class I pilus-producing strains showed reduced hybridization signals with this probe, but nevertheless retained sequences homologous to the coding sequence for the SMl epitope. However, meningococci producing class I1 pili could be divided into two groups on the basis of their reaction with the PS1 probe: half the strains tested failed to react, which is consistent with our previous analysis of silent class I pilin sequences; the remainder reacted (relatively weakly) with the probe, suggesting that the silentpil sequences in these strains extend further towards the 5' end of the pilin gene than in strains studied previously. Some strains of Neisseria lactarnica reacted weakly with both types of probe but failed to produce SM1-reactive pili. In contrast,

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“…Those parts of the fimbriae not contributing to the interaction of subunits or serving as binding sites would engage in substantial amounts of amino-acid substitutions to promote maximal immunological heterogeneity. These, presumably hypervariable, regions appear in K88 antigenic variants which, in common with P fimbriae, show variations involving "in-frame" insertions and deletions as well as single-base changes in specific regions of the structural gene (Hagblom et al, 1985), mechanisms also available to Neisseria gonorrhoeae for variation in its fimbrillar proteins (Sparling et al, 1986). The importance of P fimbriae as virulence factors in strains of E. coli responsible for acute, nonobstructive pyelonephritis has been confirmed (Domingue et al, 1985).…”

Section: Discussionmentioning

confidence: 95%

Demonstration by immuno-electronmicroscopy of antigenic heterogeneity among P fimbriae of strains of Escherichia coli

Old

Yakubu

Crichton

1987

Journal of Medical Microbiology

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Summary. The identification of P fimbriae on urinary strains of Escherichia coli isolated from urine was made (i) by observation of the patterns of mannose-resistant and eluting haemagglutination of erythrocytes of seven animal species (and including those of human p phenotype), and (ii) by haemagglutination-inhibition tests with hydatid-cyst fluid known to contain an analogue of P-fimbrial receptor. In tests with five different, pure P-fimbrial antisera prepared in rabbits, agglutinin titres of 37 Pfimbriate strains revealed differences in their reactivity ; immuno-electronmicroscopy studies with the same five antisera showed that P-fimbriate strains were markedly different in the extent to which their P fimbriae were coated with antibody. The antigenic heterogeneity observed among P fimbriae is discussed with regard to the development of P-fimbrial vaccines.

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Intragenic recombination leads to pilus antigenic variation in Neisseria gonorrhoeae

Cited by 331 publications

References 17 publications

Identification of a divergent M protein gene and an M protein-related gene family in Streptococcus pyogenes serotype 49

Identification of a divergent M protein gene and an M protein-related gene family in Streptococcus pyogenes serotype 49

Demonstration by immuno-electronmicroscopy of antigenic heterogeneity among P fimbriae of strains of Escherichia coli

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