Opacity-Associated Adhesin Repertoire in Hyperinvasive Neisseria meningitidis

Abstract

The opacity (Opa) proteins mediate a variety of interactions between the bacterium Neisseria meningitidis and its human host. These interactions are thought to be of central importance in both the asymptomatic colonization of the nasopharynx and the sporadic occurrence of meningococcal disease. The receptor specificities of a limited number of Opa protein variants have been explored, but the high level of amino acid sequence diversity among variants has complicated the assignment of specific roles to individual Opa variants or combinations of variants. In addition, the distribution of Opa protein variants among diverse meningococci, information that is potentially informative for studies of Opa function, is poorly understood. A systematic survey of the genetic diversity in the four opa gene loci in each of 77 meningococcal isolates was undertaken. These isolates were representative of the seven hyperinvasive meningococcal clonal complexes that caused the majority of meningococcal disease over the last 50 years. Consistent with previous studies, a high level of sequence diversity was observed among the opa genes and the proteins that they encoded; however, particular sets of Opa protein variants were consistently associated with each of the clonal complexes over time periods often spanning decades and during global spread. These observations were consistent with the postulate that particular combinations of Opa proteins confer fitness advantages to individual clonal complexes and have implications for studies of Opa function and the inclusion of Opa proteins in novel meningococcal vaccines.

Relative Contributions of Recombination and Mutation to the Diversification of the opa Gene Repertoire of Neisseria gonorrhoeae

“…Meningococcal isolates of the same MLST ST or clonal complex that were recovered over several decades still show considerable similarities in their opa allelic profiles (10,19), with retention of the same allele in one clonal complex over more than 50 years and, in two clonal complexes, of the same opa allelic profile in isolates recovered 25 years apart (10). The sets of meningococcal isolates studied by Callaghan et al are much more distantly related than the sets of gonococcal isolates used in this study, as the former are defined by having the same or similar allelic profiles by MLST, which indexes variation in housekeeping genes that evolve slowly, whereas the latter are defined by identity of antigen genes, which evolve very much more rapidly.…”

Opa Protein Repertoires of Disease-Causing and Carried Meningococci

“…Previous studies have identified combinations of Opa proteins consistently observed in meningococcal hyperinvasive clonal complexes over decades of epidemic spread (5,27). Hyperinvasive clonal complexes are not representative of the genetic diversity observed in asymptomatically carried meningococcal populations, however, which are composed of numerous, diverse genotypes (13,14).…”

“…Populationbased studies of Opa diversity have suggested that the meningococcal hyperinvasive clonal complexes, genotypes identified by multilocus sequence typing (MLST) and responsible for the majority of global meningococcal disease (14,20), are associated with particular Opa repertoires (5,27). It is unclear whether this association is unique to disease-causing meningococci or whether clonal complexes isolated from asymptomatic carriage that have never or rarely caused disease also exhibit this feature.…”

“…Briefly, each opa locus was amplified by PCR using locus-specific primer sets and nucleotide sequences were determined directly from PCR products. Variable-region amino acid sequence variants and sequence variants within families were identified by comparison with previously published data, and new sequence variants/variant families were assigned arbitrarily in the order of discovery, all according to previously published nomenclature (5).…”

“…Topologically, Opa proteins display an eightstranded transmembrane ␤-barrel structure with four extramembranous putative loop regions (7). A semivariable (SV) and two hypervariable (HV1 and HV2) regions are present in three of the loop regions, and a large number of Opa variants have been observed (5,22). Sequence variation, particularly in the two HV regions, influences the specificity of Opa variants for different members of the human carcinoembryonic antigen cell adhesion molecule (CEACAM) family of proteins (45,46) and cell surface saccharides (26).…”