Genetic Analysis of the Capsular Biosynthetic Locus from All 90 Pneumococcal Serotypes

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Abstract
Several major invasive bacterial pathogens are encapsulated. Expression of a polysaccharide capsule is essential for survival in the blood, and thus for virulence, but also is a target for host antibodies and the basis for effective vaccines. Encapsulated species typically exhibit antigenic variation and express one of a number of immunochemically distinct capsular polysaccharides that define serotypes. We provide the sequences of the capsular biosynthetic genes of all 90 serotypes of Streptococcus pneumoniae and relate these to the known polysaccharide structures and patterns of immunological reactivity of typing sera, thereby providing the most complete understanding of the genetics and origins of bacterial polysaccharide diversity, laying the foundations for molecular serotyping. This is the first time, to our knowledge, that a complete repertoire of capsular biosynthetic genes has been available, enabling a holistic analysis of a bacterial polysaccharide biosynthesis system. Remarkably, the total size of alternative coding DNA at this one locus exceeds 1.8 Mbp, almost equivalent to the entire S. pneumoniae chromosomal complement. Several major bacterial pathogens are coated by a polysaccharide capsule that is important for virulence. Each strain of Streptococcus pneumoniae (the pneumococcus) produces one of 90 different capsular polysaccharides, which are distinguished by using a set of antisera that recognise the chemical differences in the capsules. The capsule is important for virulence, but is immunogenic, and the large number of different capsular serotypes is believed to have been selected as a mechanism to evade the human immune response. Antibodies against capsular polysaccharide can protect against pneumococcal disease, and a highly effective protein-conjugated polysaccharide vaccine that protects children against the seven serotypes most commonly associated with serious disease has recently been introduced in the United States. Bentley and colleagues have determined the DNA sequence of the capsular biosynthesis genes for all 90 serotypes of S. pneumoniae and, by correlating the gene content with the serological profiles and with the known capsular polysaccharide structures, provide what they believe to be the most detailed and complete understanding of capsular biosynthesis and capsular gene evolution in any bacterial pathogen.