Structural properties and evolutionary relationships of PspA, a surface protein of Streptococcus pneumoniae, as revealed by sequence analysis

Yother, Janet; Briles, David E.

doi:10.1128/jb.174.2.601-609.1992

Cited by 205 publications

(208 citation statements)

References 65 publications

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“…Based on a single difference in reactivity with a panel of monoclonal antibodies, the D39 and WU2 PspAs are classified in different serotypes (serotypes 25 and 1, respectively) (9). The pspA sequences of the D39 derivatives Rx1 and R6 have been reported previously and exhibit complete identity (22,43). A comparison of the predicted N-terminal halves of the WU2 and Rx1 PspA sequences showed that despite a number of differences, the PspAs were closely related and were members of the same PspA clade (21).…”

mentioning

confidence: 94%

“…The C-terminal coding region of WU2 pspA was targeted and cloned essentially as described previously for Rx1 pspA (45). The WU2 derivative JY1123 was constructed by transformation and insertion of pKSD300, which harbors an internal 550-bp fragment from the 5Ј half of Rx1 pspA in pVA891(Em) (36,43,45). Chromosomal DNA from JY1123 was digested with HindIII, self-ligated, and transformed into E. coli, with selection for erythromycin-resistant transformants.…”

Section: Methodsmentioning

confidence: 99%

“…PspA occurs on all S. pneumoniae strains, and although variability exists, all PspAs appear to possess a signal peptide, an ␣-helical N-terminal region that contains most of the immunogenic epitopes and antigenic variability, a proline-rich domain, a choline binding domain important in anchoring the protein to the bacterial surface, and a short C-terminal tail (21,30,31,35,43). PspA reduces complement activation (40) and binds lactoferrin (16).…”

mentioning

confidence: 99%

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

2003

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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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mentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

2003

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“…A capsular type 3 pneumococcal strain (WU2, PspA ϩ ) (24,25) and its isogenic mutant (JY1119, PspA Ϫ ) (4,7,26) were used. Bacterial stocks were frozen at Ϫ80°C in Todd-Hewitt broth supplemented with 0.5% yeast extract containing 10% glycerol.…”

Section: Bacteria and Infectionsmentioning

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

107

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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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“…The PspA molecule is built from four distinct domains which include the antigenic N-terminal part followed by a highly flexible, tetherlike proline-rich region, a repeat region which is responsible for the attachment to the choline residues, and a C-terminal hydrophobic tail ( Fig. 1) (17). The N-terminal moiety likely protrudes outside of the capsule, interacts with all antibodies reactive to PspA, and has been described as the functional part of this protein (the PspA function was defined as its ability to elicit in host protective antibodies) (18,19).…”

mentioning

confidence: 99%

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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Structural properties and evolutionary relationships of PspA, a surface protein of Streptococcus pneumoniae, as revealed by sequence analysis

Cited by 205 publications

References 65 publications

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

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

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

Characterization of Selected Strains of Pneumococcal Surface Protein A

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