PspA and PspC: Their Potential for Use as Pneumococcal Vaccines

Briles, David E.; Hollingshead, Susan K.; Swiatlo, Edwin; Brooks-Walter, Alexis; Szalai, Alex J.; Virolainen, Anni; McDaniel, Larry S.; Benton, Kimberly A.; White, Peter; Prellner, Karin; Hermansson, Anne; Aerts, Piet C.; Dijk, Hans van; Crain, Marilyn J.

doi:10.1089/mdr.1997.3.401

Cited by 94 publications

(97 citation statements)

References 43 publications

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“…Previous structural studies of this domain of Rx1 PspA indicated its highly charged and polar character which has been shown to, on the one hand, stabilize PspAs interactions with the electronegative capsule through interactions with the electro-positive part of this domain and, on the other hand, points the electronegative end of PspA away from the bacterial cell wall (19). This electronegative part has already been implicated in PspAs anti-complementary properties which prevent the host complement system from attaching to S. pneumoniae (7,19). The proline-rich region of PspA likely serves as a flexible tether anchoring PspA to the cell wall through the choline-binding region (repeat region).…”

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confidence: 92%

“…It is known, however, that pneumococci produce several antigens responsible for various processes during colonization of the host. Such antigens include but are not limited to the polysaccharide capsule and proteins such as pneumococcal surface protein A (PspA) 1 (6,7) and C (PspC) (7,8), hyaluronate lyase (3,9), and pneumolysin (10). These antigens directly contribute to the invasive capability of the bacteria by allowing, for example, greater microbial access or migration between host tissues or by compromising the host defense mechanisms (7, 10 -12).…”

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confidence: 99%

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Characterization of Selected Strains of Pneumococcal Surface Protein A

Jedrzejas¹,

Lamani²,

Becker³

2001

Journal of Biological Chemistry

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Several proteins, in addition to the polysaccharide capsule, have recently been implicated in the full virulence of the Streptococcus pneumoniae bacterial pathogen. One of these novel virulence factors of S. pneumoniae is pneumococcal surface protein A (PspA). The N-terminal, cell surface exposed, and functional part of PspA is essential for full pneumococcal virulence, as evidenced by the fact that antibodies raised against this part of the protein are protective against pneumococcal infections. PspA has recently been implicated in anticomplementary function as it reduces complement-mediated clearance and phagocytosis of pneumococci. Several recombinant N-terminal fragments of PspA from different strains of pneumococci, Rx1, BG9739, BG6380, EF3296, and EF5668, were analyzed using circular dichroism, analytical ultracentrifugation sedimentation velocity and equilibrium methods, and sequence homology. Uniformly, all strains of PspA molecules studied have a high ␣-helical secondary structure content and they adopt predominantly a coiled-coil structure with an elongated, likely rod-like shape. No ␤-sheet structures were detected for any of the PspA molecules analyzed. All PspAs were found to be monomeric in solution with the exception of the BG9739 strain which had the propensity to partially aggregate but only into a tetrameric form. These structural properties were correlated with the functional, anti-complementary properties of PspA molecules based on the polar distribution of highly charged termini of its coiled-coil domain. The recombinant Rx1 PspA is currently under consideration for pneumococcal vaccine development.

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confidence: 92%

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confidence: 99%

Characterization of Selected Strains of Pneumococcal Surface Protein A

Jedrzejas¹,

Lamani²,

Becker³

2001

Journal of Biological Chemistry

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“…Pneumococcal surface protein A (PspA) 3 is an important virulence factor for S. pneumoniae (1)(2)(3). Accordingly, in a murine model of bacteremia, PspA-deficient (PspA Ϫ ) pneumococci have significantly reduced virulence compared with pneumococci that express PspA (PspA ؉ ) (2,3).…”

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confidence: 99%

The Virulence Function of Streptococcus pneumoniae Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection

Ren¹,

McCrory

Pass

et al. 2004

The Journal of Immunology

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106

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Complement is important for elimination of invasive microbes from the host, an action achieved largely through interaction of complement-decorated pathogens with various complement receptors (CR) on phagocytes. Pneumococcal surface protein A (PspA) has been shown to interfere with complement deposition onto pneumococci, but to date the impact of PspA on CR-mediated host defense is unknown. To gauge the contribution of CRs to host defense against pneumococci and to decipher the impact of PspA on CR-dependent host defense, wild-type C57BL/6J mice and mutant mice lacking CR types 1 and 2 (CR1/2−/−), CR3 (CR3−/−), or CR4 (CR4−/−) were challenged with WU2, a PspA+ capsular serotype 3 pneumococcus, and its PspA− mutant JY1119. Pneumococci also were used to challenge factor D-deficient (FD−/−), LFA-1-deficient (LFA-1−/−), and CD18-deficient (CD18−/−) mice. We found that FD−/−, CR3−/−, and CR4−/− mice had significantly decreased longevity and survival rate upon infection with WU2. In comparison, PspA− pneumococci were virulent only in FD−/− and CR1/2−/− mice. Normal mouse serum supported more C3 deposition on pneumococci than FD−/− serum, and more iC3b was deposited onto the PspA− than the PspA+ strain. The combined results confirm earlier conclusions that the alternative pathway of complement activation is indispensable for innate immunity against pneumococcal infection and that PspA interferes with the protective role of the alternative pathway. Our new results suggest that complement receptors CR1/2, CR3, and CR4 all play important roles in host defense against pneumococcal infection.

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“…Proteins are, generally, antigenically conserved across all serotypes and stimulate a T-cell-dependent immune response resulting in more robust immunological memory (28). Several pneumococcal surface proteins have been shown to be effective immunogens and can prevent sepsis, pneumonia, and carriage in animal models (1,2,5,6,23,26).…”

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Immunization with Polyamine Transport Protein PotD Protects Mice against Systemic Infection with Streptococcus pneumoniae

Shah

Swiatlo

2006

Infect Immun

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The human pathogen Streptococcus pneumoniae contains genes for a putative polyamine ABC transporter which are organized in an operon and designated potABCD. Polyamine transport protein D (PotD) is an extracellular protein which binds polyamines and possibly other structurally related molecules. PotD has been shown to contribute to virulence in both a murine sepsis model and a pneumonia model with capsular type 3 pneumococci. The protective efficacy of recombinant PotD was evaluated by active immunization and intravenous challenge with capsular type 3 pneumococci in CBA/N mice. Immunized mice had 91.7% survival following lethal pneumococcal challenge, compared with 100% mortality in the control group. Immunized animals had high-titer anti-PotD antibodies following three immunizations with alum. Protection in a sepsis model was also seen after passive administration of rabbit antiserum raised against PotD (P < 0.004). These results suggest that antibodies to PotD confer protection against invasive pneumococcal disease and that this protein should be studied further as a potential vaccine candidate for protection against invasive pneumococcal infections.

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PspA and PspC: Their Potential for Use as Pneumococcal Vaccines

Cited by 94 publications

References 43 publications

Characterization of Selected Strains of Pneumococcal Surface Protein A

Characterization of Selected Strains of Pneumococcal Surface Protein A

The Virulence Function of Streptococcus pneumoniae Surface Protein A Involves Inhibition of Complement Activation and Impairment of Complement Receptor-Mediated Protection

Immunization with Polyamine Transport Protein PotD Protects Mice against Systemic Infection with Streptococcus pneumoniae

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