Immunization with C5a Peptidase or Peptidase-Type III Polysaccharide Conjugate Vaccines Enhances Clearance of Group B Streptococci from Lungs of Infected Mice

Cheng, Qi; Debol, Steven M.; Lam, Hong; Eby, Ron; Edwards, Lorri; Matsuka, Yury V.; Olmsted, Stephen B.; Cleary, P. Patrick

doi:10.1128/iai.70.11.6409-6415.2002

Cited by 49 publications

(39 citation statements)

References 38 publications

(35 reference statements)

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“…A highly conserved protein antigen, such as LrrG, might also be used as a carrier protein for a restricted number of CPSs in order to provide greater coverage of the vaccine against clinically less important serotypes. This approach has been explored experimentally with the C protein alpha subunit and C5a peptidase of GBS conjugated to type III CPS; both of these conjugates induced protective immune responses in murine infection models (12,21). A type III GBS CPS-tetanus toxoid conjugate induced predominantly the IgG2a subclass when administered to healthy nonpregnant women (32).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to CPSs, protein antigens have the potential to elicit protective T-cell-dependent antibody responses and long-lasting immunity without the need for conjugation to other molecules. Several GBS surface proteins have already been investigated as potential vaccine candidates; these include Rib, the alpha and beta subunits of the C protein, Sip, Fbs, C5a peptidase, and the R proteins (2,12,18,20,50,80). While these antigens, with the exception of C5a peptidase and Sip, are capable of eliciting antibodies in mice and conferring a degree of protection against lethal challenge with GBS, they are not conserved among all serotypes.…”

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confidence: 99%

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Characterization of a Novel Leucine-Rich Repeat Protein Antigen from Group B Streptococci That Elicits Protective Immunity

et al. 2005

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Group B streptococci (GBS) usually behave as commensal organisms that asymptomatically colonize the gastrointestinal and urogenital tracts of adults. However, GBS are also pathogens and the leading bacterial cause of life-threatening invasive disease in neonates. While the events leading to transmission and disease in neonates remain unclear, GBS carriage and level of colonization in the mother have been shown to be significant risk factors associated with invasive infection. Surface antigens represent ideal vaccine targets for eliciting antibodies that can act as opsonins and/or inhibit colonization and invasion. Using a genetic screen for exported proteins in GBS, we identified a gene, designated lrrG, that encodes a novel LPXTG anchored surface antigen containing leucine-rich repeat (LRR) motifs found in bacterial invasins and other members of the LRR protein family. Southern blotting showed that lrrG was present in all GBS strains tested, representing the nine serotypes, and revealed the presence of an lrrG homologue in Streptococcus pyogenes. Recombinant LrrG protein was shown in vitro to adhere to epithelial cells in a dose-dependent manner, suggesting that it may function as an adhesion factor in GBS. More importantly, immunization with recombinant LrrG elicited a strong immunoglobulin G response in CBA/ca mice and protected against lethal challenge with virulent GBS. The data presented in this report suggest that this conserved protein is a highly promising candidate antigen for use in a GBS vaccine.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Characterization of a Novel Leucine-Rich Repeat Protein Antigen from Group B Streptococci That Elicits Protective Immunity

et al. 2005

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“…Studies have shown that preincubation of GBS with antibodies raised to C5a-peptidase enhances subsequent macrophage killing of the bacteria (65). Furthermore, immunization of mice with C5a-peptidase conjugated to capsular polysaccharide type III not only enhanced polysaccharidespecific antibody production, but also promoted serotypeindependent killing of GBS as assessed by the number of bacteria recovered from lungs of infected animals (66).…”

Section: C5a Peptidasementioning

confidence: 99%

Extracellular virulence factors of group B Streptococci

Liu

Nizet²

2004

Front Biosci

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“…Previous data demonstrated that ScpB is required for pulmonary colonization in a neonatal mouse model (7). However, ScpB is a bifunctional molecule, acting both as an iFn adhesin and in evading host defenses by inactivating the complement component C5a, and it is not clear which of these activities of ScpB are required for pulmonary colonization.…”

Section: Discussionmentioning

confidence: 85%

“…The streptococcal C5a peptidase (ScpB) is a cell surface endopeptidase produced by GBS that inactivates C5a (9). The role of scpB in pulmonary disease by GBS was recently investigated (7). Isogenic scpB mutant GBS strains showed a 5-log decrease in their ability to colonize the lungs of adult mice, demonstrating that scpB plays a significant role in mucosal colonization.…”

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confidence: 99%

High-Affinity Interaction between Fibronectin and the Group B Streptococcal C5a Peptidase Is Unaffected by a Naturally Occurring Four-Amino-Acid Deletion That Eliminates Peptidase Activity

Tamura¹,

Hull

Oberg³

et al. 2006

Infect Immun

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The streptococcal C5a peptidase (ScpB) of group B streptococci (GBS) is found in virtually all clinical GBS isolates and is required for mucosal colonization in a neonatal mouse model. ScpB inhibits neutrophil chemotaxis by enzymatically cleaving the complement component C5a. We previously identified a second function of ScpB as a fibronectin (Fn) adhesin using phage display. However, phage display can identify low-affinity interactions. We therefore measured the affinity of both full-length recombinant ScpB (FL-ScpB) and the 110-amino-acid phage display fragment (Scp-PDF) for immobilized Fn using surface plasmon resonance. The affinity for Fn was very high for both FL-ScpB (equilibrium dissociation constant [K D ] ‫؍‬ 4.0 nM) and Scp-PDF (K D ‫؍‬ 4.4 nM) and is consistent with a biologically significant role for the adhesin activity of ScpB. We also studied the Fn adhesin activity of a common natural variant of ScpB (ScpB⌬) that contains a 4-amino-acid deletion that eliminates peptidase activity. The integrity of scpB is otherwise maintained, suggesting that the Fn adhesin activity of ScpB may be responsible for its conservation in these strains. The affinities of both FL-ScpB⌬ (K D ‫؍‬ 2.4 nM) and ScpB⌬-PDF (K D ‫؍‬ 1.4 nM) for Fn are unaffected by the deletion. Complementation in trans by both scpB and scpB⌬ corrected the Fn-binding defect of an scpB deletion mutant GBS strain to an identical degree. The high affinity of ScpB for Fn and the maintenance of this affinity in ScpB⌬ support our hypothesis that the Fn adhesin activity of scpB plays a role in virulence.Group B streptococci (GBS) are a leading cause of sepsis and meningitis in newborns (2) and an emerging cause of serious bacterial infections in immunocompromised adults and the elderly (12). Recent advances in prevention have significantly reduced the burden of early-onset neonatal disease (onset at Ͻ7 days of age) but have not had an impact on the incidence of late-onset disease (onset at 7 to 90 days of age) (25).Evasion of host defenses is a key component of bacterial virulence. One major host defense is complement, which is involved in a variety of functions including opsonization and chemotaxis. Complement activation results in the proteolytic cleavage of C5 to generate C5a. C5a is a potent chemotactic factor that plays an important role in recruiting neutrophils to sites of inflammation. The streptococcal C5a peptidase (ScpB) is a cell surface endopeptidase produced by GBS that inactivates C5a (9). The role of scpB in pulmonary disease by GBS was recently investigated (7). Isogenic scpB mutant GBS strains showed a 5-log decrease in their ability to colonize the lungs of adult mice, demonstrating that scpB plays a significant role in mucosal colonization. These results suggested that the ability to cleave C5a is required for mucosal colonization.However, epidemiologic studies of clinical isolates of GBS called into question the role of the peptidase activity of ScpB in virulence. The scpB gene is conserved among clinical isolates, suggesting tha...

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Immunization with C5a Peptidase or Peptidase-Type III Polysaccharide Conjugate Vaccines Enhances Clearance of Group B Streptococci from Lungs of Infected Mice

Cited by 49 publications

References 38 publications

Characterization of a Novel Leucine-Rich Repeat Protein Antigen from Group B Streptococci That Elicits Protective Immunity

Characterization of a Novel Leucine-Rich Repeat Protein Antigen from Group B Streptococci That Elicits Protective Immunity

Extracellular virulence factors of group B Streptococci

High-Affinity Interaction between Fibronectin and the Group B Streptococcal C5a Peptidase Is Unaffected by a Naturally Occurring Four-Amino-Acid Deletion That Eliminates Peptidase Activity

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