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    Versinia pestis YopJ, YopT, and YopK coordinate programmed cell death and cytokine responses to promote pneumonic plague

    Olson, Rachel M.
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    [PDF] research.pdf (3.980Mb)
    [PDF] public.pdf (1.753Kb)
    Date
    2017
    Format
    Thesis
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    Abstract
    [ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Yersinia pestis has been responsible for three major pandemics of plague, including the infamous Black Death that killed 250 million people in Europe. The disease progresses rapidly due to a combination of bacterial growth and host immunopathology. During infection, Y. pestis utilizes a type III secretion system (T3SS), which is essential for virulence, to inject effector proteins that disrupt immune cell function. The majority of the Yops are dedicated to the control of programmed cell death of immune cells, namely macrophages and neutrophils, and through this, it has been proposed that initially there is immune suppression followed by an acute inflammatory response that accelerates bacterial growth and disease. Recent work has focused on the inflammasome, cellular machinery that is activated upon insertion of the translocation pore that results in host cell lysis and the release of inflammatory cytokines. In this work, we defined a novel pathogenesis mechanism involving the activation of rapid lysis of inflammatory macrophages via necroptosis by injected bacterial effectors YopT and YopJ, each with cysteine protease activity. We show that YopT is a virulence factor for plague, while deletion of YopJ had no detectable impact on virulence. Further, we found that injection of catalytically inactive YopJ induces strong activation of the inflammasome and stimulates host defense against plague. YopK modulates the effects of YopT and YopJ. Overall, it appears that induction of necroptosis by YopT and YopJ subverts the activation of the inflammasome and contributes to pathogenesis of plague.
    URI
    https://hdl.handle.net/10355/62269
    Degree
    Ph. D.
    Thesis Department
    Veterinary pathobiology (MU)
    Rights
    Access to files is limited to the University of Missouri--Columbia.
    This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License.
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    • 2017 MU dissertations - Access restricted to MU
    • Veterinary Pathobiology electronic theses and dissertations (MU)

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