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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
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    Linking Bacterial Metabolic Plasticity to Pathogenicity: The Role of Mycobacterium Intracellular Adaptation in the Suppression of Host Cell Death

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    Date
    2012
    Author
    Maxson, Michelle Elizabeth
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    Abstract
    The success of any bacterial pathogen depends greatly on the balance between pathogenicity and host antimicrobial responses. To successfully persist in a host, a bacterial pathogen must not only evade the immune response, but also metabolically adapt to the intracellular environment and the carbon sources available. Virulent Mycobacterium are able infect macrophage, and persist in the phagosome, despite a robust innate response. Interestingly for Mycobacterium, pathogenesis and virulence have been correlated to metabolic plasticity in vivo. After infection, intracellular Mycobacterium initiate global changes in bacterial gene expression, including the up-regulation of virulence factors and metabolic genes. Recent reports suggest that mycobacterial metabolic homeostasis affects the host-pathogen interaction, and the outcome of host infection.;In particular, mycobacterial metabolic dysregulation can affect macrophage viability. Mycobacterium are known to modulate several macrophage cell death pathways, which allows for the establishment of a stable environment for intracellular replication. Specifically, the de-repression of macrophage apoptosis or pyroptosis during infection results in bacterial attenuation and enhanced host immunity in vivo. Surprisingly, the known mycobacterial genes responsible for apoptosis/pyroptosis suppression primarily function in metabolism, suggesting a connection between bacterial intracellular metabolic adaptation and host cell death evasion. However, mechanistic links between Mycobacterium virulence and bacterial metabolic plasticity remain ill-defined.;The intention of this thesis was to clarify the connection between mycobacterial metabolic homeostasis and the outcome of infection. Here, a transposon mutant library of M. bovis BCG was screened for mutants that induced death in macrophage. The screen identified novel fdr ( functioning death repressor) loci that affected macrophage viability but were predicted to function in bacterial metabolism. In this thesis, the cell death induced by fdr mutants and the effects of fdr-induced immunity to M. tuberculosis were investigated. In addition, three fdr mutants were chosen for further mechanistic studies which suggest that the balance of bacterial redox in the intracellular environment is critical for Mycobacterium pathogenicity. Taken together, the studies from this thesis have expanded the subset of known Mycobacterium genes linking bacterial metabolic plasticity to pathogenicity and persistence, a relationship key to the evolved success of M. tuberculosis as a human pathogen.
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    https://yulib002.mc.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3531912
    https://hdl.handle.net/20.500.12202/1335
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    • Albert Einstein College of Medicine: Doctoral Dissertations [1674]

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