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Lipopolysaccharide and Alginate in Muciod Pseudomonas Aeruginosa

Davis Jr., Michael R
Format
Thesis/Dissertation; Online
Author
Davis Jr., Michael R
Advisor
Goldberg, Joanna B
Abstract
Polysaccharides are critical for the pathogenesis of many bacteria, including the Gram - negative pathogens Pseudomonas aeruginosa and the closely related species that comprise the Burkholderia cepacia complex (Bcc). These species are responsible for a majority of the often fatal lung infections in cystic fibrosis (CF) patients - yet their pathogenesis can proceed in very different manners. P. aeruginosa typically forms lifelong chronic infections that can last decades, while Bcc infections can be acute. Chronic infections caused by P. aeruginosa are characterized by a series of genotypic and phenotypic changes that are thought to be selected for in the harsh conditions of the CF lung and that contribute to its chronicity. Two major differences in polysaccharide expression between acute and chronic P. aeruginosa infection isolates are that chronic strains overexpress the exopolysaccharide alginate (rendering them mucoid) and have defects in LPS expression. Here, we identify a mutation responsible for the temperature-sensitive LPS phenotype of a chronic P. aeruginosa CF isolate, strain 2192. We use this strain, and other defined laboratory wild - type and mutant strains to demonstrate that there is a correlation between mucoidy and a loss of high molecular weight (HMW) LPS with long O - antigen side chains. In addition, RT - qPCR analyses on these strains point to a potential positive feedback loop that links alginate synthesis with transcription of LPS biosynthetic genes, including the O - antigen chain length regulators wzzl and wzz2. In separate collaborative studies, we investigate the LPS phenotypes of an outbreak of Burkholderia dolosa and the clinical relevance of the secreted polysaccharide Poly - N - acetyl glucosamine (PNAG) by Burkholderia cepacia. Both of these Burkholderia species are members of the Bcc and have been shown to be highly antibiotic resistant and vi capable of causing life - threatening infections. The data we generated through these separate collaborative efforts reVeal new genes involved in pathogenesis and highlight the possibility of noVel therapeutic treatments that target polysaccharides of the Bcc. Taken together, the data presented below help to clarify mechanisms and regulation of polysaccharide synthesis in these important pathogens.
Language
English
Published
University of Virginia, Department of Microbiology, Immunology, and Cancer Biology, PHD (Doctor of Philosophy), 2013
Published Date
2013-03-01
Degree
PHD (Doctor of Philosophy)
Collection
Libra ETD Repository
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