Lab Research Focus
The main focus of our research is on the capsular polysaccharides of Streptococcus pneumoniae, a Gram-positive pathogen that is a major etiologic agent of many human infections, including pneumonia, meningitis, and otitis media. The capsular polysaccharides represent the single most important virulence factor of S. pneumoniae, and their characterization has historically played an important role in the development of bacterial genetics and the understanding of bacterial virulence mechanisms. My lab studies the genetics, biochemistry, and virulence properties of these polysaccharides. Using genetic analyses, we have identified and characterized the serotype 3 capsule locus, which encodes the enzymes necessary for synthesizing a repeating glucose-glucuronic acid polymer. Our present studies are directed towards developing a better understanding of the mechanism of type 3 polysaccharide synthesis, identifying both the genetic and enzymatic bases for regulation of capsule expression, characterizing the specific mechanism by which the capsule affords protection against host immune defenses, and analyzing the regulation of capsule expression in animal models of infection. Also of major importance to these studies is the analysis of how capsule synthesis is linked to other essential cellular pathways. We are also characterizing similar properties for the serotype 2 capsule, which represents a more complex polysaccharide and genetic structure, has a different mechanism of polysaccharide synthesis, and utilizes different mechanisms of regulation than the serotype 3 capsule. Synthesis of the serotype 2 capsule involves an assembly apparatus that is comprised of multiple proteins. We are using genetic and biochemical analyses to identify the members of this complex and to determine their role in capsule formation. The biosynthetic mechanism for the serotype 2 capsule is representative of most of the 93 S. pneumoniae capsular polysaccharides, as well as capsules and exopolysaccharides from other streptococci and Gram-positive bacteria, as well as capsules and O-antigens from Gram-negative bacteria. In contrast, the serotype 3 capsule is similar to cellulose, chitin, and hyaluronan from both prokaryotic and eukaryotic organisms. Thus, the study of these two capsule serotypes provides broad insights into polysaccharide genetics, synthesis, and regulation in both prokaryotic and eukaryotic organisms.
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