The polysaccharide capsule of Streptococcus pneumoniae is the major virulence determinant of this organism. Despite early studies of the genetics, pathogenesis, and immunology of capsular polysaccharides, it remains unclear why certain capsular types appear to have a greater capacity to cause disease. Of the more than 80 known capsular serotypes, 23 account for more than 90% of all pneumococcal infections. The basis for emergence of new capsule types remains equally obscure. Whether influenced by mutation, recombination, or immune selection, genetic exchange of DNA among S. pneumoniae strains is likely to have played a major role in the evolution of capsular types. The long range goals of the proposed studies are to determine the effect of capsular type on the virulence of Streptococcus pneumoniae, to determine the genetic organization and regulation of capsule genes, and to determine the basis for genetic switching of capsule type gene cassettes. These studies will allow for the development of more effective strategies for treating and preventing pneumococcal infections, as they reveal how the capsular type of an invading strain might influence the effectiveness of vaccines or other therapies. Genetic and now molecular studies have indicated that the capsule type- specific genes are linked in the chromosome and that they are transferred and exchanged as a unit during genetic transformation. The genetic locus responsible for type 3 capsule expression has been identified through mutation, cloning, and sequence analyses. Flanking, non-type-specific DNA, present in all strains and likely to be involved in the recombination and switching of capsule types, has been located at one end of the region. In the proposed studies, the type 3 locus will be further characterized with respect to the type-specific genes, the non-type- specific DNA flanking each side of the region, and the factors involved in regulation of type 3 capsule expression. Genetic exchange of the chromosomal regions containing the type-specific genes has allowed us to construct near isogenic strains differing in the capsule type expressed. Initial studies indicate that virulence may be altered by the capsule type but non-capsular factors influence how different serotypes affect virulence. In the proposed studies, isogenic strains representing different capsular and genetic backgrounds will be constructed using defined PCR- or restriction fragments that contain the type-specific gene cassettes. These strains will be used to determine the effect of capsule type on mouse virulence and on in vitro measures of pneumococcal virulence, including phagocytosis and complement fixation. These studies will ultimately allow us to characterize the capsule genes of all capsular types, and to identify the structural features resulting in differences in virulence.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028457-09
Application #
2671963
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Project Start
1989-07-01
Project End
2000-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
9
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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James, David B A; Yother, Janet (2012) Genetic and biochemical characterizations of enzymes involved in Streptococcus pneumoniae serotype 2 capsule synthesis demonstrate that Cps2T (WchF) catalyzes the committed step by addition of ?1-4 rhamnose, the second sugar residue in the repeat unit. J Bacteriol 194:6479-89
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Yother, Janet (2011) Capsules of Streptococcus pneumoniae and other bacteria: paradigms for polysaccharide biosynthesis and regulation. Annu Rev Microbiol 65:563-81
Kaufman, Greer E; Yother, Janet (2007) CcpA-dependent and -independent control of beta-galactosidase expression in Streptococcus pneumoniae occurs via regulation of an upstream phosphotransferase system-encoding operon. J Bacteriol 189:5183-92
Xayarath, Bobbi; Yother, Janet (2007) Mutations blocking side chain assembly, polymerization, or transport of a Wzy-dependent Streptococcus pneumoniae capsule are lethal in the absence of suppressor mutations and can affect polymer transfer to the cell wall. J Bacteriol 189:3369-81
Ventura, Christy L; Cartee, Robert T; Forsee, W Thomas et al. (2006) Control of capsular polysaccharide chain length by UDP-sugar substrate concentrations in Streptococcus pneumoniae. Mol Microbiol 61:723-33

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