Relative Roles of Genetic Background and Variation in PspA in the Ability of Antibodies to PspA To Protect against Capsular Type 3 and 4 Strains of Streptococcus pneumoniae

ABSTRACT Pneumococcal surface protein A (PspA) is able to elicit antibodies in mice and humans that can protect mice against fatal infection with Streptococcus pneumoniae. It has been observed that immunization with a single family 1 PspA can protect mice against infections with capsular type 3 or 6B strains expressing PspA family 1 or 2. However, several studies have shown that immunity to PspA is less efficacious against several capsular type 4 strains than against strains of capsular types 3, 6A, and 6B. To determine whether the greater difficulty in protecting against capsular type 4 strains resulted from differences in their PspAs or from differences in their genetic backgrounds, we performed protection experiments using four different challenge strains: a capsular type 3 strain expressing a family 1 PspA (WU2), a capsular type 4 strain expressing a family 2 PspA (TIGR4), and genetically engineered variants of WU2 and TIGR4 expressing each other's PspAs. Prior to infection, the mice were immunized with recombinant family 1 or family 2 PspA. The results revealed that much of the difficulty in protecting against capsular type 4 strains was eliminated when mice were immunized with a homologous PspA of the same PspA family. However, regardless of which PspA the strains expressed, those on the TIGR4 background were about twice as hard to protect against as WU2 strains expressing the same PspA based on the efficacy rates seen in our experiments. These results point out the importance of including more than one PspA in any PspA vaccines developed for human use.

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Genetic Alteration of Capsule Type but Not PspA Type Affects Accessibility of Surface-Bound Complement and Surface Antigens of Streptococcus pneumoniae

Infection and Immunity ◽

10.1128/iai.71.1.218-225.2003 ◽

2003 ◽

Vol 71 (1) ◽

pp. 218-225 ◽

Cited By ~ 92

Author(s):

Melanie Abeyta ◽

Gail G. Hardy ◽

Janet Yother

Keyword(s):

Streptococcus Pneumoniae ◽

Immune Responses ◽

Protein A ◽

Surface Protein ◽

Surface Antigens ◽

Capsular Polysaccharides ◽

Capsule Type ◽

Type 3 ◽

Determining Factor

ABSTRACT The Streptococcus pneumoniae capsular polysaccharides and pneumococcal surface protein A (PspA) are major determinants of virulence that are antigenically variable and capable of eliciting protective immune responses. By genetically switching the pspA genes of the capsule type 2 strain D39 and the capsule type 3 strain WU2, we showed that the different abilities of antibody to PspA to protect against these strains was not related to the PspA type expressed. Similarly, the level of specific antibody binding to PspA, other surface antigens, and surface-localized C3b did not depend on the PspA type but instead was correlated with the capsule type. The type 3 strain WU2 and an isogenic derivative of D39 that expresses the type 3 capsule bound nearly identical amounts of antibody to PspA and other surface antigens, and these amounts were less than one-half the amount observed with the type 2 parent strain D39. Expression of the type 3 capsule in D39 also reduced the amount of C3b deposited and its accessibility to antibody, resulting in a level intermediate between the levels observed with WU2 and D39. Despite these effects, the capsule type was not the determining factor in anti-PspA-mediated protection, as both D39 and its derivative expressing the type 3 capsule were more resistant to protection than WU2. The specific combination of PspA and capsule type also did not determine the level of protection. The capsule structure is thus a major determinant in accessibility of surface antigens to antibody, but certain strains appear to express other factors that can influence antibody-mediated protection.

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Immunization with a plasmid expressing pneumococcal surface protein A (PspA) can elicit protection against fatal infection with Streptococcus pneumoniae

Gene Therapy ◽

10.1038/sj.gt.3300401 ◽

1997 ◽

Vol 4 (4) ◽

pp. 375-377 ◽

Cited By ~ 20

Author(s):

LS McDaniel ◽

F Loechel ◽

C Benedict ◽

T Greenway ◽

DE Briles ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Protein A ◽

Surface Protein ◽

Fatal Infection ◽

Pneumococcal Surface Protein A

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Relationship between Surface Accessibility for PpmA, PsaA, and PspA and Antibody-Mediated Immunity to Systemic Infection by Streptococcus pneumoniae

Infection and Immunity ◽

10.1128/iai.73.3.1304-1312.2005 ◽

2005 ◽

Vol 73 (3) ◽

pp. 1304-1312 ◽

Cited By ~ 57

Author(s):

Dennis O. Gor ◽

Xuedong Ding ◽

David E. Briles ◽

Michael R. Jacobs ◽

Neil S. Greenspan

Keyword(s):

Streptococcus Pneumoniae ◽

Capsular Polysaccharide ◽

Protein A ◽

Age Groups ◽

Pneumococcal Infection ◽

Systemic Infection ◽

Surface Protein ◽

Target Antigen ◽

Age Related ◽

Type 3

ABSTRACT Antibodies to capsular polysaccharide (PS) are protective against systemic infection by Streptococcus pneumoniae, but the large number of pneumococcal serogroups and the age-related immunogenicity of pure PS limit the utility of PS-based vaccines. In contrast, cell wall-associated proteins from different capsular serotypes can be cross-reactive and immunogenic in all age groups. Therefore, we evaluated three pneumococcal proteins with respect to relative accessibility to antibody, in the context of intact pneumococci, and their ability to elicit protection against systemic infection by encapsulated S. pneumoniae. Sequences encoding pneumococcal surface adhesin A (PsaA), putative protease maturation protein A (PpmA), and the N-terminal region of pneumococcal surface protein A (PspA) from S. pneumoniae strain A66.1 were cloned and expressed in Escherichia coli. The presence of genes encoding PsaA, PpmA, and PspA in 11 clinical isolates was examined by PCR, and the expression of these proteins by each strain was examined by Western blotting with antisera raised to the respective recombinant proteins. We used flow cytometry to demonstrate that PspA was readily detectable on the surface of the pneumococcal strains analyzed, whereas PsaA and PpmA were not. Consistent with these observations, mice with passively or actively acquired antibodies to PspA or type 3 PS were equivalently protected from homologous systemic challenge with type 3 pneumococci, whereas mice with passively or actively acquired antibodies to PsaA or PpmA were not effectively protected. These experiments support the hypothesis that the extent of protection against systemic pneumococcal infection is influenced by target antigen accessibility to circulating host antibodies.

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DNA vaccines expressing pneumococcal surface protein A (PspA) elicit protection levels comparable to recombinant protein

Journal of Medical Microbiology ◽

10.1099/jmm.0.46217-0 ◽

2006 ◽

Vol 55 (4) ◽

pp. 375-378 ◽

Cited By ~ 14

Author(s):

Daniela M. Ferreira ◽

Eliane N. Miyaji ◽

Maria Leonor S. Oliveira ◽

Michelle Darrieux ◽

Ana Paula M. Arêas ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Recombinant Protein ◽

Dna Vaccines ◽

Protein A ◽

Surface Protein ◽

Humoral Response ◽

Cost Effective ◽

Promising Candidate ◽

Pneumococcal Surface Protein A ◽

Antibody Levels

Pneumococcal surface protein A (PspA) is a promising candidate for the development of cost-effective vaccines against Streptococcus pneumoniae. In the present study, BALB/c mice were immunized with DNA vaccine vectors expressing the N-terminal region of PspA. Animals immunized with a vector expressing secreted PspA developed higher levels of antibody than mice immunized with the vector expressing the antigen in the cytosol. However, both immunogens elicited similar levels of protection against intraperitoneal challenge. Furthermore, immunization with exactly the same fragment in the form of a recombinant protein, with aluminium hydroxide as an adjuvant, elicited even higher antibody levels, but this increased humoral response did not correlate with enhanced protection. These results show that DNA vaccines expressing PspA are able to elicit protection levels comparable to recombinant protein, even though total anti-PspA IgG response is considerably lower.

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Pneumococcal Surface Protein C Contributes to Sepsis Caused by Streptococcus pneumoniae in Mice

Infection and Immunity ◽

10.1128/iai.72.5.3077-3080.2004 ◽

2004 ◽

Vol 72 (5) ◽

pp. 3077-3080 ◽

Cited By ~ 47

Author(s):

Francesco Iannelli ◽

Damiana Chiavolini ◽

Susanna Ricci ◽

Marco Rinaldo Oggioni ◽

Gianni Pozzi

Keyword(s):

Streptococcus Pneumoniae ◽

Protein C ◽

Lethal Dose ◽

Surface Protein ◽

Infection Model ◽

Wild Type ◽

Mutant Strains ◽

Type 3

ABSTRACT The role of pneumococcal surface protein C (PspC; also called SpsA, CbpA, and Hic) in sepsis by Streptococcus pneumoniae was investigated in a murine infection model. The pspC gene was deleted in strains D39 (type 2) and A66 (type 3), and the mutants were tested by being injected intravenously into mice. The animals infected with the mutant strains showed a significant increase in survival, with the 50% lethal dose up to 250-fold higher than that for the wild type. Our findings indicate that PspC affords a decisive contribution to sepsis development.

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