The capsular polysaccharides of Streptococcus pneumoniae are essential virulence determinants for this organism. They serve as the basis for serologic classification, with ninety serotypes being distinguished to date, and they are the target for protective antibodies. In both human infections and animal models, virulence is related to the serotype of the capsule expressed. The mechanisms underlying the virulence differences between serotypes are not known but may involve both the polysaccharide structures and other factors in the genetic background in which they are expressed. Molecular genetic studies have identified a common organization among the different S. pneumoniae capsule loci. This organization permits the exchange of capsular serotypes during transformation, leading to new combinations of virulence factors and potentially impacting on the efficacy of polysaccharide-based vaccines. Knowledge of the genetic components of the loci has permitted pathways for polysaccharide synthesis to be demonstrated or proposed. Often, enzymes expected to be essential for capsule production are not encoded by genes in these loci, and the necessary products are obtained from cellular pools contributing to pathways for peptidoglycan and teichoic acid synthesis. Thus, capsule expression and basic cellular functions are intimately linked. Recent studies have demonstrated a requirement for capsule in colonization but have suggested that capsule production is reduced in this environment as compared to other host environments. Expression of other factors important for adherence and sustained colonization may be elevated during colonization and reduced at other times. Coordinate regulation of these virulence factors is thus anticipated and recent studies have identified a surface component potentially involved in adherence whose expression is altered in response to changes in capsule production. In the proposed studies, we will continue the genetic analysis of virulence and capsule expression.
The specific aims are to: 1) determine the effect of specific alterations in capsule type and structure on virulence, 2) characterize the requirement for capsule in pneumococcal infections and its expression in vitro and in vivo, and 3) characterize regulatory networks and cellular pathways associated with capsule synthesis.
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