Pneumococcal Virulence Factors: Structure and Function

Jedrzejas, Mark J.

doi:10.1128/mmbr.65.2.187-207.2001

Cited by 411 publications

(378 citation statements)

References 170 publications

(181 reference statements)

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“…Such additional protection might also be independent of the serotypes, as it seems to be the case for PspA at least in the investigated animal models (20). Therefore, the development of either a protein antigen(s)-based vaccine or a two-component vaccine comprising a polysaccharide and a nonpolysaccharide part, such as a protein discussed above, PspA, might be the best approach (20,(43)(44)(45)(46).…”

Section: Polysaccharide-based Vaccines and Other Approaches To Develomentioning

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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Section: Polysaccharide-based Vaccines and Other Approaches To Develomentioning

confidence: 99%

Characterization of Selected Strains of Pneumococcal Surface Protein A

Jedrzejas¹,

Lamani²,

Becker³

2001

Journal of Biological Chemistry

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“…In S. pneumoniae, hyaluronate lyase, neuraminidases, autolysin, choline-binding protein A, and pneumococcal surface protein A are suggested to function as cell surface virulent factors (12). Hyaluronate lyase degrades the extracellular matrix component hyaluronan in mammalian cells through the ␤-elimination reaction and releases unsaturated disaccharide, indicating that the enzyme produced by pathogenic bacteria functions as a spreading factor (13).…”

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confidence: 99%

Substrate Specificity of Streptococcal Unsaturated Glucuronyl Hydrolases for Sulfated Glycosaminoglycan

Maruyama

Nakamichi²,

Itoh³

et al. 2009

Journal of Biological Chemistry

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Unsaturated glucuronyl hydrolase (UGL) categorized into the glycoside hydrolase family 88 catalyzes the hydrolytic release of an unsaturated glucuronic acid from glycosaminoglycan disaccharides, which are produced from mammalian extracellular matrices through the ␤-elimination reaction of polysaccharide lyases. Here, we show enzyme characteristics of pathogenic streptococcal UGLs and structural determinants for the enzyme substrate specificity. The putative genes for UGL and phosphotransferase system for amino sugar, a component of glycosaminoglycans, are assembled into a cluster in the genome of pyogenic and hemolytic streptococci such as Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes, which produce extracellular hyaluronate lyase as a virulent factor. The UGLs of these three streptococci were overexpressed in Escherichia coli cells, purified, and characterized. Streptococcal UGLs degraded unsaturated hyaluronate and chondroitin disaccharides most efficiently at approximately pH 5.5 and 37°C. Distinct from Bacillus sp. GL1 UGL, streptococcal UGLs preferred sulfated substrates. DNA microarray and Western blotting indicated that the enzyme was constitutively expressed in S. agalactiae cells, although the expression level increased in the presence of glycosaminoglycan. The crystal structure of S. agalactiae UGL (SagUGL) was determined at 1.75 Å resolution by x-ray crystallography. SagUGL adopts ␣ 6 /␣ 6 -barrel structure as a basic scaffold similar to Bacillus UGL, but the arrangement of amino acid residues in the active site differs between the two. SagUGL Arg-236 was found to be one of the residues involved in its activity for the sulfated substrate through structural comparison and site-directed mutagenesis. This is the first report on the structure and function of streptococcal UGLs.

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“…Pneumolysin (PLY), a 53-kDa protein toxin produced by virtually all clinical isolates of S. pneumoniae, has been regarded as a key virulence factor of this bacterium (7) and as one of the candidates for vaccine development against pneumococcal infection (21). PLY is one of the cholesterol-dependent cytolysins (24) that are known to form ring-or arc-shaped pores on cholesterol-containing membranes and whose activity is blocked by free cholesterol (40,50).…”

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confidence: 99%

Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection withStreptococcus pneumoniaeIn Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

et al. 2008

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Pneumolysin is a pore-forming cytolysin known as a major virulence determinant of Streptococcus pneumoniae. This protein toxin has also been shown to activate the Toll-like receptor 4 (TLR4) signaling pathway. In this study, a mutant S. pneumoniae strain deficient in pneumolysin (⌬ply) and a recombinant pneumolysin protein (rPLY) were constructed. Upon infection of macrophages in vitro, the ability to induce the production of interleukin-1␣ (IL-1␣), IL-1␤, and IL-18 was severely impaired in the ⌬ply mutant, whereas there was no marked difference in the induction of tumor necrosis factor alpha (TNF-␣) and IL-12p40 between the wild type and the ⌬ply mutant of S. pneumoniae. When macrophages were stimulated with rPLY, the production of IL-1␣, IL-1␤, and IL-18 was strongly induced in a TLR4-dependent manner, whereas lipopolysaccharide, a canonical TLR4 agonist, hardly induced these cytokines. In contrast, lipopolysaccharide was more potent than rPLY in inducing the production of TNF-␣, IL-6, and IL-12p40, the cytokines requiring no caspase activation. Activation of caspase-1 was observed in macrophages stimulated with rPLY but not in those stimulated with lipopolysaccharide, and the level of activation was higher in macrophages infected with wild-type S. pneumoniae than in those infected with the ⌬ply mutant. These results clearly indicate that pneumolysin plays a key role in the host response to S. pneumoniae, particularly in the induction of caspase-1-dependent cytokines.

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Pneumococcal Virulence Factors: Structure and Function

Cited by 411 publications

References 170 publications

Characterization of Selected Strains of Pneumococcal Surface Protein A

Characterization of Selected Strains of Pneumococcal Surface Protein A

Substrate Specificity of Streptococcal Unsaturated Glucuronyl Hydrolases for Sulfated Glycosaminoglycan

Critical Involvement of Pneumolysin in Production of Interleukin-1α and Caspase-1-Dependent Cytokines in Infection withStreptococcus pneumoniaeIn Vitro: a Novel Function of Pneumolysin in Caspase-1 Activation

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