Staphylococcus aureus capsular polysaccharides

Abstract

Serotype 5 and 8 capsular polysaccharides predominate among clinical isolates of Staphylococcus aureus. The results of experiments in animal models of infection have revealed that staphylococcal capsules are important in the pathogenesis of S. aureus infections. The capsule enhances staphylococcal virulence by impeding phagocytosis, resulting in bacterial persistence in the bloodstream of infected hosts. S. aureus capsules also promote abscess formation in rats. Although the capsule has been shown to modulate S. aureus adherence to endothelial surfaces in vitro, animal studies suggest that it also promotes bacterial colonization and persistence on mucosal surfaces. S. aureus capsular antigens are surface associated, limited in antigenic specificity, and highly conserved among clinical isolates. With the emergence of vancomycin-resistant S. aureus in the United States in 2002, new strategies are needed to combat staphylococcal infections. Purified serotype 5 and 8 capsular polysaccharides offer promise as target antigens for a vaccine to prevent staphylococcal infections, although the inclusion of other antigens is likely to be essential in the development of an effective S. aureus vaccine. The genetics and mechanisms of capsule biosynthesis are complex, and much work remains to enhance our understanding of capsule biosynthesis and its regulation.

FIG. 1.

Serum antibodies to CP1 in groups of mice immunized intraperitoneally with either phosphate-buffered saline (PBS), 10⁸ CFU of formalin-killed S. aureus SA1 mucoid, or CP1. Arrows denote immunizations, and each point represents the mean ELISA index (± standard error) of serum diluted 1:100. The ELISA index was calculated by dividing the absorbance reading of the test serum by the absorbance reading of a pool of high-titered immune mouse serum (raised to killed SA1 mucoid). Data are from reference .

FIG. 2.

Active immunization with formalin-killed cells of S. aureus SA1 mucoid or CP1 protects mice against lethality induced by various challenge doses of strain SA1 mucoid. Data are from reference .

FIG. 3.

Transmission electron micrographs of S. aureus cells cultured on agar plates. Prior to fixation, both strains were incubated with rabbit CP5-specific antibodies to stabilize and visualize the capsule. (A) CP5-producing strain Reynolds; (B) acapsular S. aureus mutant.

FIG. 4.

SCCcap1 and flanking sequences from S. aureus strain M. Vertical arrowheads represent attachment sites of the SCCcap1 element. The cap1 operon is shown by double-headed arrows, as is the Ψccr gene complex of three open reading frames conserved among SCCmec elements. A novel enterotoxin gene (ent) and a truncated transposase gene (trp*) identified outside of the SCCcap1 are indicated by short arrows. The DNA region to the left of the ent gene is homologous to a gene region found in NCTC 8325, but many of the open reading frames within this region contain mutations. Data are adapted from Luong et al. (74).

FIG. 5.

Comparison of S. aureus cap5 and cap8 gene clusters. The cap5 sequence was derived from strains Newman and Reynolds, and the cap8 sequence was derived from strain Becker as shown. Gene designations are shown in boxes. Percent identity indicates the amino acid identity of the deduced proteins of the two clusters. Both gene clusters are transcribed from left to right. Data are from reference .

FIG. 6.

Proposed pathway for the biosynthesis of S. aureus CP5. The gene products for which functions have been experimentally determined are shown in boxes. UDP-d-GlcNAc, UDP-2-acetamido-2-deoxy-d-glucose or UDP-N-acetyl-d-glucosamine; UDP-d-ManNAc, UDP-2-acetamido-2-deoxy-d-mannose or UDP-N-acetyl-d-mannosamine; UDP-l-FucNAc, UDP-2-acetamido-2,6-dideoxy-l-galactose or UDP-N-acetyl-l-fucosamine; UDP-d-ManNAcA, UDP-2-acetamido-2-deoxy-d-mannuronic acid or UDP-N-acetyl-d-mannosaminuronic acid; UDP-d-QuiNAc, UDP-2-acetamido-2,6-dideoxy-d-glucose or UDP-N-acetyl-d-quinovosamine; UDP-l-6dTalNAc, UDP-2-acetamido-2,6-dideoxy-l-talose or UDP-N-acetyl-l-pneumosamine.