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Joanna Marshall Dissertation.pdf (12.85 MB)

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The O-Antigen Capsule of Salmonella Typhimurium in Acute and Chronic Infection

Marshall, Joanna M.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1385998769

Abstract Details

2013, Doctor of Philosophy, Ohio State University, Integrated Biomedical Science Graduate Program.
Salmonella Typhimurium, similarly to other enteric pathogens, produce a group IV O-antigen (O-ag) capsule exhibiting structural resemblance to the lipopolysaccharide (LPS). Polysaccharide capsules are known virulence factors of many bacterial pathogens, facilitating evasion of immune recognition and systemic dissemination during acute infection. Capsular polysaccharides can also aid establishment of chronic infection and environmental spread of disease by increasing bacterial surface adherence, self-aggregation and resistance to stress, all of which are critical steps in the continued cycle of infection. In this work, we sought to further characterize the O-ag capsule, a recently described surface polysaccharide of Salmonella Typhimurium. We have established that functional surface assembly of the O-ag capsule shares several common enzymatic pathways with lipopolysaccharide (LPS) biosynthesis and that disruption of the O-ag capsule does not interfere with production of LPS. Whole cell imaging has revealed heterogeneous capsular expression within sessile and biofilm bacterial populations and indicates that capsular expression may shield recognition of the LPS O-ag by specific antibodies. Additionally, we have observed that absence of the O-ag capsule results in dysregulated surface expression of highly immunostimulatory phase I flagellin (FliC) and increases bacterial susceptibility to killing by human serum. Due to their high level of attenuation, strains lacking the alternative RNA polymerase sigma factor RpoS have been extensively investigated for possible future inclusion in a live vaccine strain and the currently licensed live-attenuated vaccine strain for Salmonella Typhi TY21A is RpoS-deficient. Efforts to produce attenuated vaccines with RpoS-deficient phenotypes have focused on achieving a balance of attenuation and immunogenicity, reporting that a lack of systemic replication of rpoS mutants necessitates multiple doses of greater than 10^10CFU to achieve moderate protection against subsequent infection. We have observed in a murine model of acute infection that yihO mutants carrying an inactivating mutation in rpoS exhibit efficient systemic dissemination without restoration of virulence and that inoculation with this live attenuated strain is able to provide high-level, long lasting protection against fatal infection after a single oral dose. Additional studies were conducted to better understand the role of the O-ag capsule and Vi-ag capsule in chronic disease and gallstone biofilm formation, which has been shown to facilitate carriage. In order to better characterize the extracellular matrix, we have developed a method of sectioning Salmonella biofilms grown ex vivo on the surface of human gallstones, permitting direct visualization of individual matrix components. We have established that although neither O-ag capsule nor Vi-ag capsule are required for systemic dissemination or gallstone/cholesterol biofilm formation, both exhibit characteristics in vitro that may facilitate these infectious stages. Furthermore, both capsules are abundantly detected within the extracellular matrix of gallstone biofilms, indicating a novel non-structural role for these polysaccharides in chronic infection. Collectively these data indicate that the O-ag capsule is a distinct accessory surface polysaccharide expressed by a subset of cells, potentially facilitating acute and chronic infection by mediating evasion of detection and killing by the host immune system.
John Gunn, PhD (Advisor)
Robert Munson, PhD (Committee Member)
Jesse Kwiek, PhD (Committee Member)
Daniel Wozniak, PhD (Committee Member)
151 p.
Biomedical Research; Microbiology; Molecular Biology
Microbial Pathogenesis; Salmonella Typhi; Salmonella Typhimurium; O antigen capsule; Biofilm; Lipopolysaccharide; Flagella;

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Citations

  • Marshall, J. M. (2013). The O-Antigen Capsule of Salmonella Typhimurium in Acute and Chronic Infection [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385998769

    APA Style (7th edition)

  • Marshall, Joanna. The O-Antigen Capsule of Salmonella Typhimurium in Acute and Chronic Infection. 2013. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1385998769.

    MLA Style (8th edition)

  • Marshall, Joanna. "The O-Antigen Capsule of Salmonella Typhimurium in Acute and Chronic Infection." Doctoral dissertation, Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1385998769

    Chicago Manual of Style (17th edition)

osu1385998769
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© 2013, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.