Pneumococcal Capsules and Their Types: Past, Present, and Future

Abstract

Streptococcus pneumoniae (the pneumococcus) is an important human pathogen. Its virulence is largely due to its polysaccharide capsule, which shields it from the host immune system, and because of this, the capsule has been extensively studied. Studies of the capsule led to the identification of DNA as the genetic material, identification of many different capsular serotypes, and identification of the serotype-specific nature of protection by adaptive immunity. Recent studies have led to the determination of capsular polysaccharide structures for many serotypes using advanced analytical technologies, complete elucidation of genetic basis for the capsular types, and the development of highly effective pneumococcal conjugate vaccines. Conjugate vaccine use has altered the serotype distribution by either serotype replacement or switching, and this has increased the need to serotype pneumococci. Due to great advances in molecular technologies and our understanding of the pneumococcal genome, molecular approaches have become powerful tools to predict pneumococcal serotypes. In addition, more-precise and -efficient serotyping methods that directly detect polysaccharide structures are emerging. These improvements in our capabilities will greatly enhance future investigations of pneumococcal epidemiology and diseases and the biology of colonization and innate immunity to pneumococcal capsules.

FIG 1

Serotype 11A as a representative of Wzy-dependent PS synthesis. (A) cps gene organization and putative functions of the gene products (based on GenBank accession no. CR931653.1). We have utilized the genetic nomenclature of Salmonella O-antigen synthesis used by Bentley et al. (30) but have included common gene nomenclature in parentheses. The cps locus occurs between dexB and aliA in the chromosome. (B) Putative biochemical steps of synthesis for the serotype 11A repeat unit (shown in the inset). Synthesis begins with the transfer of glucose-1-phosphate to an undecaprenyl phosphate (UndP) acceptor (1), and the repeat unit is sequentially assembled by glycosyltransferases (2). Cytoplasmic acetyltransferases place acetyl groups on some monosaccharide moieties (3) before export (4) and polymerization (5). The completed unit is decorated by transmembrane acetyltransferases before and/or after polymerization (6). The inset shows the biochemical structure of serotype 11A PS, and degree of acetylation is indicated in red. Abbreviations: Gro, glycerol; Gal, galactose; Glc, glucose.

FIG 2

Serotype 3 has a divergent cps locus and utilizes synthase-dependent assembly. (A) The serotype 3 cps locus (based on GenBank accession no. CR931634.2). The cps locus occurs between dexB and aliA on the chromosome. Note that ugd (cps3D) and wchE (cps3S) are necessary for capsular synthesis, and wzd, galU, and pgm (*) are dispensable (66, 73, 74, 275, 276). (B) The Cps3S synthase synthesizes serotype 3 PS (structure shown in the inset). Cps3S initiates synthesis by transfer of glucose (Glc) from UDP-glucose to a phosphatidyl glycerol (PG) acceptor (1), transfers glucuronic acid (GlcUA) from UDP-GlcUA to the PG-linked Glc (2), and extends the capsule to approximately an octosaccharide (3). Under favorable conditions (i.e., relatively high [GlcUA]), Cps3S translocates the PS chain to the external face of the membrane (4) and increases chain length by a processive capsular synthesis mechanism (5). PS is thought to be released when [GlcUA] becomes insufficient to fill the second-sugar binding site of Cps3S before the PS chain advances without a new sugar to bind in the first binding site.