All ETDs from UAB

Advisory Committee Chair

Janet Yother

Advisory Committee Members

William Benjamin

Kevin Dybvig

Hubert Tse

Hui Wu

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Streptococcus pneumoniae is a gram-positive bacterial pathogen that causes diseases such as pneumonia, meningitis, bacteremia and middle ear infections. The major virulence factor of S. pneumoniae is its polysaccharide capsule. The capsule enables the organism to evade host defenses by providing protection against complement-mediated opsonophagocytosis in systemic sites and by allowing the organism to successfully colonize the nasopharynx. The nasopharynx is the natural reservoir of S. pneumoniae. In the nasopharynx, S. pneumoniae is in a high oxygen (O2) environment, however when it has the opportunity to bypass host defenses and invade systemic sites, it reaches environments with low O2. Capsule production seems to correlate with O2 availability. In high O2, capsule production is decreased, however it increases with decreasing O2 availability. In this project, we propose that capsule production may be modulated through the production of hydrogen peroxide (H2O2). Under high O2 growth, S. pneumoniae produces large quantities (can be >1 mM) of hydrogen peroxide (H2O2) due primarily to the activity of SpxB, a pyruvate oxidase. SpxB is an important virulence factor but little is known about its direct function in pathogenesis. An spxB deletion mutant generated in these studies exhibited increased capsule production compared to the parent under both high and low oxygen conditions. The addition of exogenous H2O2 (0.5 mM) to the culture medium restored capsule production to near parental levels. The effect of H2O2 appears to be posttranslational, as levels of capsule biosynthesis proteins were unaffected in the spxB mutant. However, in vitro activity of the initiating glycosyltransferase for capsule synthesis was increased in the spxB mutant compared to the parent following growth under high oxygen. Generation of the oxidizing agent H2O2 may serve as a regulatory signal for capsule production, through response of capsule enzymes to oxidizing and reducing conditions.

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