Date of Award
Doctor of Philosophy (PhD)
Microbiology and Immunology
The polysaccharide capsule of Streptococcus pneumoniae (the pneumococcus) is its most important virulence factor, without which it is unable to cause lethal infections. Importantly, the pneumococcus must change the size of its capsule as it traverses different environments within the host, thereby allowing for both adherence during colonization and protection from host defenses during invasive disease. Although much has been accomplished in identifying how capsular polysaccharides are synthesized and attached to the cell wall, few reports have lent insight into how the genes responsible for capsule synthesis (the cps locus) are transcriptionally regulated. Here, we describe the mechanism by which two conserved transcription factors, SpxR and CpsR, regulate pneumococcal capsule synthesis during infection through a novel, cis-regulatory element within the cps promoter regulatory region, the 37-CE. Biochemical, genetic, and structural data suggest a model in which SpxR and CpsR repress capsule synthesis until the pneumococcus reaches the blood, where we hypothesize changes in central metabolism cause signaling events that lead to de-repression, allowing for the increased capsule production required for survival in this environment. In search of regulatory signals, we go on to characterize the SpxR regulon using chromatin immunoprecipitation followed by sequencing (ChIP-seq). This method identified key central metabolic enzymes as additional regulatory targets of SpxR and determined its activities are influenced by environmental oxygen. Expanding these studies to the Gram-positive pathogens Staphylococcus aureus and Listeria monocytogenes assisted in the identification of a regulatory SpxR ligand, describing, for the first time, a possible function for this molecule. Taken together, this work suggests SpxR coordinates pneumococcal capsule expression with central metabolism, likely in an oxygen-dependent manner. Excitingly, conservation of the SpxR regulon and its signaling mechanisms in S. aureus and L. monocytogenes suggest SpxR is functionally conserved.
Glanville, David George, "Regulatory Mechanisms Controlling Pneumococcal Capsule Synthesis" (2023). Dissertations. 4023.
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Copyright © 2023 David George Glanville
Available for download on Sunday, April 27, 2025