Streptococcus agalactiae Alpha-Like Protein 1 Possesses Both Cross-Reacting and Alp1-Specific Epitopes

Kvam, A. I.; Mavenyengwa, Rooyen T.; Radtke, Andreas; Mæland, Johan A.

doi:10.1128/cvi.05005-11

Cited by 9 publications

(12 citation statements)

References 32 publications

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“…Furthermore, smaller amounts of antibodies against alpha and Rib proteins, present in the host, have also been reported to be associated with a higher incidence of disease (67). Therefore, alpha-like proteins have been considered potential antigens for the development of a vaccine against GBS (67)(68)(69). Here, we observed a 4-fold increase in the expression of the rib gene following incubation in whole human blood, leading to a high level of expression of this immunogenic protein.…”

Section: Discussionsupporting

confidence: 52%

Whole-Genome Comparison Uncovers Genomic Mutations between Group B Streptococci Sampled from Infected Newborns and Their Mothers

Almeida¹,

Villain

Joubrel

et al. 2015

J Bacteriol

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Streptococcus agalactiae (group B Streptococcus or GBS), a commensal of the human gut and genitourinary tract, is a leading cause of neonatal infections, in which vertical transmission from mother to child remains the most frequent route of contamination. Here, we investigated whether the progression of GBS from carriage to disease is associated with genomic adaptation. Whole-genome comparison of 47 GBS samples from 19 mother-child pairs uncovered 21 single nucleotide polymorphisms (SNPs) and seven insertions/deletions. Of the SNPs detected, 16 appear to have been fixed in the population sampled whereas five mutations were found to be polymorphic. In the infant strains, 14 mutations were detected, including two independently fixed variants affecting the covRS locus, which is known to encode a major regulatory system of virulence. A one-nucleotide insertion was also identified in the promoter region of the highly immunogenic surface protein Rib gene. Gene expression analysis after incubation in human blood showed that these mutations influenced the expression of virulence-associated genes. Additional identification of three mutated strains in the mothers' milk raised the possibility of the newborns also being a source of contamination for their mothers. Overall, our work showed that GBS strains in carriage and disease scenarios might undergo adaptive changes following colonization. The types and locations of the mutations found, together with the experimental results showing their phenotypic impact, suggest that those in a context of infection were positively selected during the transition of GBS from commensal to pathogen, contributing to an increased capacity to cause disease. IMPORTANCEGroup B Streptococcus (GBS) is a major pathogen responsible for neonatal infections. Considering that its colonization of healthy adults is mostly asymptomatic, the mechanisms behind its switch from a commensal to an invasive state are largely unknown. In this work, we compared the genomic profile of GBS samples causing infections in newborns with that of the GBS colonizing their mothers. Multiple mutations were detected, namely, within key virulence factors, including the response regulator CovR and surface protein Rib, potentially affecting the pathogenesis of GBS. Their overall impact was supported by differences in the expression of virulence-associated genes in human blood. Our results suggest that during GBS's progression to disease, particular variants are positively selected, contributing to the ability of this bacterium to infect its host. Streptococcus agalactiae, or group B Streptococcus (GBS), is currently regarded as one of the leading causes of neonatal sepsis and meningitis worldwide (1-4). Known as a commensal of the digestive and genitourinary tracts of 10 to 30% of the human population, GBS is also a significant source of disease in immunocompromised adults and in the elderly (4-7). Apart from causing human infections, GBS is an etiological agent of bovine mastitis and invasive disease in fish (8-10). F...

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Section: Discussionsupporting

confidence: 52%

Whole-Genome Comparison Uncovers Genomic Mutations between Group B Streptococci Sampled from Infected Newborns and Their Mothers

Almeida¹,

Villain

Joubrel

et al. 2015

J Bacteriol

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“…For example, immunization with a C␣ with as many as 16 repeats failed to induce anti-N-terminalregion antibodies and also affected the protective activity of the antibodies elicited (19,22,29). Similar observations have been made in our laboratory (31). Immunization with purified recombinant C␣ N terminus or the N terminus as part of a fusion protein resulted in a strong antibody response when the immunogenicity of the C␣ N terminus was not suppressed by multiple C-terminal repeats (22,29).…”

supporting

confidence: 67%

“…AAJP00000000) and sequences from the strain A909 bca (GenBank accession no. M97256) were aligned, it was found that the Alp1 and C␣ repeats were virtually identical (31). This explains why the C-terminal regions from Alp1 and C␣ behaved immunologically as two identical antigens, including the ability of both repeat regions to bind a monoclonal antibody raised against the C␣ from A909 (31).…”

mentioning

confidence: 75%

“…The N-terminal region of the product of bca, the gene encoding C␣, showed 70% homology with the N termini of the products of alp2 and alp3 and 60% homology with the Rib N terminus, but antibodies against the corresponding proteins showed no immunological cross-reactivity with C␣ (22,31,32,33). This should imply that the C␣ N terminus induces C␣-specific antibodies when used for immunization without being bound to the C␣ C terminus with multiple repeats.…”

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confidence: 91%

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Survey of Immunological Features of the Alpha-Like Proteins of Streptococcus agalactiae

Mæland

Afset

Lyng

et al. 2014

Clin. Vaccine Immunol.

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bNearly all Streptococcus agalactiae (group B streptococcus [GBS]) strains express a protein which belongs to the so-called alphalike proteins (Alps), of which C␣, Alp1, Alp2, Alp3, Rib, and Alp4 are known to occur in GBS. The Alps are chimeras which form mosaic structures on the GBS surface. Both N-and C-terminal stretches of the Alps possess immunogenic sites of dissimilar immunological specificity. In this review, we have compiled data dealing with the specificity of the N-and C-terminal immunogenic sites of the Alps. The majority of N-terminal sites show protein specificity while the C-terminal sites show broader cross-reactivity. Molecular serotyping has revealed that antibody-based serotyping has often resulted in erroneous Alp identification, due to persistence of cross-reacting antibodies in antisera for serotyping. Retrospectively, this could be expected on the basis of sequence analysis results. Some of the historical R proteins are in fact Alps. The data included in the review may provide a basis for decisions regarding techniques for the preparation of specific antisera for serotyping of GBS, for use in other approaches in GBS research, and for decision making in the context of GBS vaccine developments.

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“…However, the immunological uniqueness of the proteins Z1, Z2, and R3, indicated by the data of this and earlier studies (9,11), suggests that it may become possible to develop molecular typing methods for specific detection of each of the protein-encoding genes, perhaps by including primer sets for the genes in a multiplex PCR. This prediction is based on data which indicate that at least some strain-variable GBS genes which can be identified by gene-specific PCR often encode proteins which possess protein-specific epitopes (20,21,28,29). Knowledge of the usefulness of Z1, Z2, and R3 determination in GBS serotyping is sparse and unknown for GBS from most areas of the world (9)(10)(11)(12)30).…”

Section: Discussionmentioning

confidence: 99%

Novel Aspects of the Z and R3 Antigens of Streptococcus agalactiae Revealed by Immunological Testing

Mæland

Radtke

Lyng

et al. 2013

Clin Vaccine Immunol

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Group B streptococci (GBS) are important human and bovine pathogens which can be classified by a variety of phenotype-and gene-based techniques. The capsular polysaccharide and strain-variable, surface-anchored proteins are particularly important phenotypic markers. In an earlier study, a previously unrecognized protein antigen called Z was described. It was expressed by 27.2% of GBS strains from Zimbabwe, usually in combination with R3 protein expression. In this study, a putative Z-specific antiserum actually contained antibodies against two different antigens named Z1 and Z2; Z1 was >250 kDa in molecular mass. Z1, Z2, and R3 generated multiple stained bands on Western blots and showed similar chromatographic characteristics with respect to molecular mass, aggregate formation, and charge. Of 28 reference and prototype GBS strains examined, 8/28 (28.5%) isolates expressed one, two, or all three of the Z1, Z2, and R3 antigens; 4/28 expressed all three antigens; 2/28 expressed Z2 and R3; 1/28 expressed Z1 only; and 1/28 expressed R3 only. Twenty (71.5%) of the 28 isolates expressed none of the three antigens. Expression of one or more of these antigens was shown by isolates of the capsular polysaccharide types Ia, Ib, V, and IX and NT strains and occurred in combination with expression of various other strain-variable and surface-localized protein antigens. When used as serosubtype markers, Z1, Z2, and R3 affected existing GBS serotype designations for some of the isolates. For instance, the R3 reference strain Prague 10/84 (ATCC 49447) changed serotype markers from V/R3 to V/R3, Z1, and Z2. Other isolates may change correspondingly, implying consequences for GBS serotyping and research. S ubspecies classification of Streptococcus agalactiae (group B streptococci [GBS]) is important in epidemiological settingsand in efforts to identify highly virulent variants of the bacterium, which is an important pathogen in humans, notably in neonates. A variety of typing techniques have been used for this purpose, such as phenotypic marker-based and/or gene-based techniques. For instance, by use of antibody-based and molecular methods such as multilocus sequence typing (MLST) (1) or restriction digest pattern (RDP) typing (2), GBS clones with particularly high virulence for neonates have been identified (1, 2). The highly virulent variants have been associated with a gene called srr-2 and expression of a surface-linked marker, the ε antigen, which may contribute to the increased virulence (3). Other gene elements and gene products also characterize the highly virulent GBS isolates (4, 5). In addition to a core genome shared by all GBS, GBS genomes contain a large number of strain-variable genes which may encode virulence factors such as strain-variable and surface-linked proteins which may function as adhesins and/or invasins, as targets of protective antibodies (meaning potential vaccine candidates), as enzymes, and as markers for serosubtyping of GBS already serotyped on the basis of the capsular polysaccharide (CPS) antig...

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Streptococcus agalactiae Alpha-Like Protein 1 Possesses Both Cross-Reacting and Alp1-Specific Epitopes

Cited by 9 publications

References 32 publications

Whole-Genome Comparison Uncovers Genomic Mutations between Group B Streptococci Sampled from Infected Newborns and Their Mothers

Whole-Genome Comparison Uncovers Genomic Mutations between Group B Streptococci Sampled from Infected Newborns and Their Mothers

Survey of Immunological Features of the Alpha-Like Proteins of Streptococcus agalactiae

Novel Aspects of the Z and R3 Antigens of Streptococcus agalactiae Revealed by Immunological Testing

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