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    Clostridioides difficile Toxins Impact Intestinal Monolayer Tight Junctions and Barrier Function

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    azu_etd_18555_sip1_m.pdf
    Embargo:
    2023-01-14
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    Author
    Jillella, Shobitha
    Issue Date
    2020
    Keywords
    bacterial toxins
    Clostridioides difficile
    Clostridium difficile
    Advisor
    McCarthy, Fiona
    
    Metadata
    Show full item record
    Publisher
    The University of Arizona.
    Rights
    Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction, presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
    Embargo
    Release after 01/14/2023
    Abstract
    Clostridioides difficile is the leading cause of antibiotic-associated diarrhea in the US. C. difficile-associated infection is precipitated by the antibiotic suppression of the normal intestinal flora and causes mild to life-threatening diarrhea. C. difficile produces up to three toxins: toxins A and B (TcdA and TcdB), and C. difficile transferase toxin. Many subtypes of TcdB exist, including the canonical TcdB1 and the isoform TcdB2, found in some outbreak-associated C. difficile strains. These toxins are essential for virulence and cause diarrhea; they inhibit actin polymerization and cause cell death in intestinal epithelial cells (IECs). Though there is some evidence of toxin-mediated disruption of tight junction integrity and paracellular barrier function, the extent to which TcdA, TcdB1, and TcdB2 differentially impact tight junctions and the intestinal epithelial barrier has not been fully elucidated. We hypothesize that these C. difficile toxins differentially impact the localization and abundance of the tight junction protein occludin and its associated adaptor, tight junction-associated protein 1 (also ZO-1), and perturb the intestinal epithelial barrier. While immunoblotting and densitometric analysis of cells treated with TcdA, TcdB1, or TcdB2 show that occludin and ZO-1 abundance are unaltered, immunofluorescence of toxin-treated cells demonstrates that occludin and ZO-1 are relocalized and that TcdB1 impacts occludin and ZO-1 distribution than TcdB2. Time courses measuring transepithelial electrical resistance across polarized cell monolayers demonstrate significant differences in resistance falls between apical and basolateral toxin treatments. From these studies, we conclude that TcdA, TcdB1, and TcdB2 differentially impact the distribution of the tight junction protein occludin and its associated adapter, ZO-1, as well as barrier function. Overall, TcdB1 affected tight junction protein distribution and barrier function to a greater degree than TcdB2. We also demonstrated that, globally, receptor polarity impacts toxin-mediated barrier function loss.
    Type
    text
    Electronic Thesis
    Degree Name
    M.S.
    Degree Level
    masters
    Degree Program
    Graduate College
    Microbiology
    Degree Grantor
    University of Arizona
    Collections
    Master's Theses

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