Deletion of Repeats in the Alpha C Protein Enhances the Pathogenicity of Group B Streptococci in Immune Mice

Gravekamp, Claudia; Rosner, Bernard; Madoff, Lawrence C.

doi:10.1128/iai.66.9.4347-4354.1998

Cited by 51 publications

(20 citation statements)

References 29 publications

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“…The surface proteins play an important role in the pathogenesis of GBS infection. It has been shown that strains passing from mother to neonate may undergo mutations in bca, encoding a-C-protein, and that these mutations coincide with a loss of susceptibility to antibody-mediated killing by polymorphonuclear leukocytes [44,45].…”

Section: Discussionmentioning

confidence: 99%

Characterisation of invasive group B streptococci based on investigation of surface proteins and genes encoding surface proteins

Persson

Berg

Bevanger

et al. 2008

Clinical Microbiology and Infection

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The joint distributions of the six genes bca, bac, epsilon/alp1, alp2, alp3 and rib (encoding alpha-C-protein, beta-C-protein, epsilon/Alp1, Alp2, Alp3, and Rib, respectively) and the proteins alpha-C-protein, beta-C-protein and Rib were investigated in invasive isolates of group B streptococcus (GBS). In total, 297 invasive isolates (123 from neonates, 174 from adults) from south-west Sweden were collected during a 13-year period. Genes were detected using multiplex and specific PCRs, and expression of the surface proteins was demonstrated using monoclonal antibodies. The genes studied were found alone or in combinations in 294 (99%) of the invasive isolates. The most common genes were rib (n = 127 isolates, 43%), alp3 (n = 78, 26%) and epsilon/alp1 (n = 42, 14%). The bac gene was never found alone, but was found in combination with one other gene in 36 isolates. The surface proteins studied were detected alone or in combinations in 152 (51%) isolates, with the most common being Rib (n = 80, 27%), alpha-C-protein (n = 68, 23%) and beta-C-protein (n = 24, 8%). Several genes were associated significantly with particular serotypes (e.g., epsilon/alp1 with serotype Ia; bca and bac with serotypes Ib and II; rib with serotype III; alp3 with serotype V). Overall, it was concluded that demonstration of different genes and surface proteins of GBS strains can be useful in epidemiological studies and in formulation of vaccines, but disappointingly, no single gene or surface protein included in the study was sufficiently common for it to be considered as the basis for a successful GBS vaccine.

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Section: Discussionmentioning

confidence: 99%

Characterisation of invasive group B streptococci based on investigation of surface proteins and genes encoding surface proteins

Persson

Berg

Bevanger

et al. 2008

Clinical Microbiology and Infection

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“…It is apparent that the repeat domains in both C␣ and Rib are subject to insertions and deletions due to homologous recombination. There is some evidence that strains of GBS expressing C␣ antigens with fewer repeat domains are less susceptible to the host immune response than are those that express C␣ antigens containing larger numbers of repeats (280,510). Conversely, it has been shown that C␣ proteins with fewer repeat domains are more immunogenic (278,279).…”

Section: Streptococcus Agalactiae (Group B Streptococci)mentioning

confidence: 99%

Surface Proteins of Gram-Positive Bacteria and Mechanisms of Their Targeting to the Cell Wall Envelope

Navarre

Schneewind

1999

Microbiol Mol Biol Rev

1,186

601

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SUMMARY The cell wall envelope of gram-positive bacteria is a macromolecular, exoskeletal organelle that is assembled and turned over at designated sites. The cell wall also functions as a surface organelle that allows gram-positive pathogens to interact with their environment, in particular the tissues of the infected host. All of these functions require that surface proteins and enzymes be properly targeted to the cell wall envelope. Two basic mechanisms, cell wall sorting and targeting, have been identified. Cell well sorting is the covalent attachment of surface proteins to the peptidoglycan via a C-terminal sorting signal that contains a consensus LPXTG sequence. More than 100 proteins that possess cell wall-sorting signals, including the M proteins of Streptococcus pyogenes, protein A of Staphylococcus aureus, and several internalins of Listeria monocytogenes, have been identified. Cell wall targeting involves the noncovalent attachment of proteins to the cell surface via specialized binding domains. Several of these wall-binding domains appear to interact with secondary wall polymers that are associated with the peptidoglycan, for example teichoic acids and polysaccharides. Proteins that are targeted to the cell surface include muralytic enzymes such as autolysins, lysostaphin, and phage lytic enzymes. Other examples for targeted proteins are the surface S-layer proteins of bacilli and clostridia, as well as virulence factors required for the pathogenesis of L. monocytogenes (internalin B) and Streptococcus pneumoniae (PspA) infections. In this review we describe the mechanisms for both sorting and targeting of proteins to the envelope of gram-positive bacteria and review the functions of known surface proteins.

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“…However, the size of the protein, which corresponds to the number of repeats, varies in clinical GBS isolates (25,28). Using a neonatal mouse model, we have shown that the number of repeats is important for vaccine efficacy (11)(12)(13). Alpha C proteins containing 1 or 2 repeats are more protective when used for passive (11) or active (12) immunization than are alpha C proteins with 9 or 16 repeats.…”

mentioning

confidence: 99%

Alpha C Protein as a Carrier for Type III Capsular Polysaccharide and as a Protective Protein in Group B Streptococcal Vaccines

Gravekamp¹,

Kasper

Paoletti³

et al. 1999

Infect Immun

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The alpha C protein, a protective surface protein of group B streptococci (GBS), is present in most non-type III GBS strains. Conjugate vaccines composed of the alpha C protein and type III capsular polysaccharide (CPS) might be protective against most GBS infections. In this study, the type III CPS was covalently coupled to full-length, nine-repeat alpha C protein (resulting in III-α9r conjugate vaccine) or to two-repeat alpha C protein (resulting in III-α2r conjugate vaccine) by reductive amination. Initial experiments with the III-α9r vaccine showed that it was poorly immunogenic in mice with respect to both vaccine antigens and was suboptimally efficacious in providing protection in mice against challenge with GBS. Therefore, modified vaccination protocols were used with the III-α2r vaccine. Female mice were immunized three times with 0.5, 5, or 20 μg of the III-α2r vaccine with an aluminum hydroxide adjuvant and bred. Ninety-five percent of neonatal mice born to dams immunized with the III-α2r vaccine survived challenge with GBS expressing type III CPS, and 60% survived challenge with GBS expressing wild-type (nine-repeat) alpha C protein; 18 and 17%, respectively, of mice in the negative control groups survived (P, <0.0001). These protection levels did not differ significantly from those obtained with the type III CPS-tetanus toxoid conjugate vaccine and the unconjugated two-repeat alpha C protein, which protected 98 and 58% of neonates from infection with GBS expressing type III CPS or the alpha C protein, respectively. Thus, the two-repeat alpha C protein in the vaccine was immunogenic and simultaneously enhanced the immunogenicity of type III CPS. III-α vaccines may be alternatives to GBS polysaccharide-tetanus toxoid vaccines, eliciting additional antibodies protective against GBS infection.

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Deletion of Repeats in the Alpha C Protein Enhances the Pathogenicity of Group B Streptococci in Immune Mice

Cited by 51 publications

References 29 publications

Characterisation of invasive group B streptococci based on investigation of surface proteins and genes encoding surface proteins

Characterisation of invasive group B streptococci based on investigation of surface proteins and genes encoding surface proteins

Surface Proteins of Gram-Positive Bacteria and Mechanisms of Their Targeting to the Cell Wall Envelope

Alpha C Protein as a Carrier for Type III Capsular Polysaccharide and as a Protective Protein in Group B Streptococcal Vaccines

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