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PorA variable regions of Neisseria meningitidis.

ABSTRACT: Subtypes, defined by variation in the outer membrane protein PorA, are an integral part of the characterization scheme for Neisseria meningitidis. Identification of these variants remains important as the PorA protein is a major immunogenic component of several meningococcal vaccines under development, and characteristics of PorA are used to provide detailed epidemiologic information. Historically, serosubtypes have been defined by reactivity with a set of monoclonal antibodies. However, nucleotide sequence analyses of porA genes have established that the panel of serosubtyping monoclonal antibodies is not exhaustive, and many porA variants cannot be detected. In addition, the nomenclature system used to define subtypes is inadequate. We examined all available nucleotide sequences of the porA VR1 and VR2 regions to identify and define subtype families. A revised nomenclature scheme, compatible with the previous serologic nomenclature scheme, was devised. A Web-accessible database describing this nomenclature and its relationship to previous schemes was established (available from: http://neisseria.org/nm/typing/pora).

SUBMITTER: Russell JE

PROVIDER: S-EPMC3323080 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Proposed standardization of Neisseria meningitidis PorA variable-region typing nomenclature.

Project description:Neisseria meningitidis isolates are conventionally classified by serosubtyping, which characterizes the reactivities of the PorA outer membrane protein variable-region (VR) epitopes with monoclonal antibodies (MAbs). A newer method (PorA VR typing) uses predicted amino acid sequences derived from DNA sequence analysis. The resulting classification schemes are not standardized, offering conflicting and sometimes irreconcilable data from the two methods. In this paper, we propose a standardization of the PorA VR typing nomenclature that incorporates serologic information from traditional PorA serosubtyping with molecular data from predicted VR sequences. We performed a comprehensive literature and database search, generating a collection of strains and DNA sequences that reflects the diversity within PorA that exists to date. We have arranged this information in a comprehensive logical model that includes both serosubtype and PorA VR type assignments. Our data demonstrate that the current panel of serosubtype-defining MAbs underestimates PorA VR variability by at least 50%. Our proposal for VR typing is informative because amino acid sequence and serologic information, when serosubtype-defining MAbs are available, can be deduced simultaneously from the PorA VR designation. This scheme will be useful in future classification and applied epidemiologic studies of N. meningitidis, being a systematic way of selecting PorA vaccine candidates and analyzing vaccine coverage and failure.

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Functional activities and immunoglobulin variable regions of human and murine monoclonal antibodies specific for the P1.7 PorA protein loop of Neisseria meningitidis.

Project description:The meningococcal PorA protein is considered a promising vaccine candidate. Although much is understood regarding the structure of PorA proteins, little is known about the structure-function relationships of PorA antibodies. The aim of this study was to compare the functional and molecular characteristics of a human monoclonal antibody (MAb) and three murine MAbs specific for the PorA P1.7 serosubtype. Murine MAbs 207,B-4 (immunoglobulin G2a [IgG2a]) and MN14C11.6 (IgG2a) were both bactericidal and opsonophagocytic for P1.7-expressing meningococci, whereas human MAb SS269 (IgG3) and murine MAb 208,D-5 (IgA) initiated neither effector function. Epitope mapping with synthetic peptides revealed that MAbs 207,B-4 and 208,D-5 recognized the sequence ASGQ, which is the same specificity motif that a previous study had established for SS269 and MN14C11.6. Nucleotide and amino acid sequence analyses of the variable regions of the four MAbs showed that the SS269 V(H) region belonged to the VH3 family and was approximately 70% homologous to those of the murine MAbs which were all from the 7183 family, whereas the SS269 V(L) region belonged to the Vlambda1-b family and was less than 40% homologous to those of the murine MAbs which were all members of the Vkappa1 family. The Fab fragment of SS269 was cloned and expressed in Escherichia coli and was shown by enzyme-linked immunosorbent assay analyses to bind as well as intact SS269 MAb to P1.7,16 serosubtype group B strain 44/76. We conclude that distinct differences exist in the effector function activities and variable region gene sequences of human and murine P1.7-specific MAbs despite their recognition of similar epitopes.

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PorA variable antigenic regions VR1, VR2, and VR3 of Neisseria meningitidis serogroups B and C isolated in Brazil from 1999 to 2004.

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Neisseria meningitidis porA, fetA and fHbp gene distribution in Western Australia 2000 to 2011.

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Mapping the laminin receptor binding domains of Neisseria meningitidis PorA and Haemophilus influenzae OmpP2.

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| S-EPMC3457995 | biostudies-literature

Deletion of porA by recombination between clusters of repetitive extragenic palindromic sequences in Neisseria meningitidis.

Project description:PorA is an important component in a vaccine against infection with Neisseria meningitidis. However, porA-negative meningococci were isolated from patients, thereby potentially limiting the role of PorA-mediated immunity. To analyze the mechanism by which the porA deletion occurred, the regions upstream and downstream of porA from three meningococcal strains (H44/76, H355, and 860183) were sequenced. The porA upstream region in strain 860183 contains a cluster of 22 repetitive palindromic RS3 core sequences (ATTCCC-N8-GGGAAT) and 10 RS3 core sequences (ATTCCC) in direct orientation. The cluster is flanked by neisserial repeats, so-called Correia elements, and can be subdivided into three repeats of 518 bp followed by a truncated repeat. The porA upstream region of the other two strains showed deletions, probably caused by a recombination between RS3 core sequences. The porA downstream region of H44/76 and H355 contains the IS1106 element followed by a cluster of 10 palindromic RS3 core sequences, 4 RS3 core sequences, and 1 other RS3 core sequence (GGGAAT) and is followed by a Correia element. This cluster can be subdivided into four direct repeats of 370 bp. Strain 860183 had two such repeats instead of four. Sequence analysis of the porA-negative variants indicated that the deletion of porA occurred via a recombination between two copies of the 116-bp region, containing two palindromic RS3 core sequences and a single RS3 core sequence. This region is homologous in the upstream and downstream clusters.

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Sequence variation in the porA gene of a clone of Neisseria meningitidis during epidemic spread.

Project description:The ET-15 clone within the electrophoretic type (ET)-37 complex of Neisseria meningitidis was first detected in Canada in 1986 and has since been associated with outbreaks of meningococcal disease in many parts of the world. While the majority of the strains of the ET-37 complex are serosubtype P1.5,2, serosubtype determination of ET-15 strains may often be incomplete, with either only one or none of the two variable regions (VRs) of the serosubtype PorA outer membrane protein reacting with monoclonal antibodies. DNA sequence analysis of the porA gene from ET-15 strains with one or both unidentified serosubtype determinants was undertaken to identify the genetic basis of the lack of reaction with the monoclonal antibodies. Fourteen different porA alleles were identified among 38 ET-15 strains from various geographic origins. The sequences corresponding to subtypes P1.5a,10d, P1.5,2, P1.5,10d, P1.5a,10k, and P1.5a,10a were identified in 18, 11, 2, 2, and 1 isolate, respectively. Of the remaining four strains, which all were nonserosubtypeable, two had a stop codon within the VR1 and the VR2, respectively, while in the other two the porA gene was interrupted by the insertion element, IS1301. Of the strains with P1.5,2 sequence, one had a stop codon between the VR1 and VR2, one had a four-amino-acid deletion outside the VR2, and another showed no expression of PorA on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Our results reveal that numerous genetic events have occurred in the porA gene of the ET-15 clone in the short time of its epidemic spread. The magnitude of microevolutionary mechanisms available in meningococci and the remarkable genetic flexibility of these bacteria need to be considered in relation to PorA vaccine development.

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Phase variation of PorA, a major outer membrane protein, mediates escape of bactericidal antibodies by Neisseria meningitidis.

Project description:Several outer membrane proteins of Neisseria meningitidis are subject to phase variation due to alterations in simple sequence repeat tracts. The PorA protein is a major outer membrane protein and a target for protective host immune responses. Phase variation of PorA is mediated by a poly-G repeat tract present within the promoter, leading to alterations in protein expression levels. N. meningitidis strain 8047 was subjected to serial passage in the presence of P1.2, a PorA-specific bactericidal monoclonal antibody. Rapid development of resistance to bactericidal activity was associated with a switch in the PorA repeat tract from 11G to 10G. Phase variants with a 10G repeat tract exhibited a 2-fold reduction in surface expression of PorA protein. A mutS mutant of strain 8047, with an elevated phase variation rate, exhibited a higher rate of escape and an association of escape with 10G and 9G variants, the latter having a 13-fold reduction in surface expression of PorA. We conclude that graduated reductions in the surface expression of outer membrane proteins mediated by phase variation enable meningococci to escape killing in vitro by bactericidal antibodies. These findings indicate how phase variation could have a major impact on immune escape and host persistence of meningococci.

| S-EPMC3639595 | biostudies-literature

Analysis of Neisseria meningitidis class 3 outer membrane protein gene variable regions and type identification using genetic techniques.

Project description:The class 3 porin proteins of Neisseria meningitidis stimulate bactericidal antibodies and express serotype-specific antigenic epitopes. Sequence analysis of porB genes for the class 3 proteins revealed regions of variability that map to surface-exposed loops. To evaluate the relationship between serotype and variable-region (VR) genotype, sequences from the 11 class 3-expressing serotype strains and 3 additional serotype 4 strains were analyzed by molecular techniques. Multiple-sequence alignment revealed a limited number of unique sequences at each of four VRs (VR1 to VR4), ranging from four unique sequences at VR1 to seven sequence patterns at VR2 and VR4. Serotype-specific VR sequences were found in each of the four VRs, suggesting that each VR has immunologic importance. Five serotypes had at least one VR sequence that was unique. Three serotypes which had sequences in common with other serotypes at each VR were distinguished by examining multiple VRs. Serotype 3 was identical to serotype 19 at each VR, and serotype 8 was identical to serotype 18 at each VR. Serotypes 4 and 21 were identical at VR1 and significantly different at VR3 and VR4. A subpopulation of serotype 4 strains with a unique VR2 sequence was identified. The serotypes which were grouped with closely related or identical sequences at one VR were grouped with different serotypes at other VRs consistent with the pattern of genetic mosaicism described for the porA (class 1 protein) gene. Hybridization assays demonstrated the ability to identify VR genotypes and distinguish serotypes using biotin-labelled oligonucleotide probes. This information may be useful in strain selection for vaccine development, in epidemiologic studies to determine the prevalence of the individual VR genotype (especially among nonserotypeable strains) and, combined with PCR, in the identification of culture-negative suspected meningococcal cases.

| S-EPMC173179 | biostudies-other

Oral administration of recombinant Neisseria meningitidis PorA genetically fused to H. pylori HpaA antigen increases antibody levels in mouse serum, suggesting that PorA behaves as a putative adjuvant.

Project description:The Neisseria meningitidis outer membrane protein PorA from a Chilean strain was purified as a recombinant protein. PorA mixed with AbISCO induced bactericidal antibodies against N. meningitidis in mice. When PorA was fused to the Helicobacter pylori HpaA antigen gene, the specific response against H. pylori protein increased. Splenocytes from PorA-immunized mice were stimulated with PorA, and an increase in the secretion of IL-4 was observed compared with that of IFN-?. Moreover, in an immunoglobulin sub-typing analysis, a substantially higher IgG1 level was found compared with IgG2a levels, suggesting a Th2-type immune response. This study revealed a peculiar behavior of the purified recombinant PorA protein per se in the absence of AbISCO as an adjuvant. Therefore, the resistance of PorA to proteolytic enzymes, such as those in the gastrointestinal tract, was analyzed, because this is an important feature for an oral protein adjuvant. Finally, we found that PorA fused to the H. pylori HpaA antigen, when expressed in Lactococcus lactis and administered orally, could enhance the antibody response against the HpaA antigen approximately 3 fold. These observations strongly suggest that PorA behaves as an effective oral adjuvant.

| S-EPMC4514328 | biostudies-literature

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