Inflammasomes and Cytotoxic Lymphocytes Clear Bacteria From Different Intracellular Niches Public Deposited

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  • March 21, 2019
Creator
  • Maltez, Vivien
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Programmed cell death is a powerful anti-microbial defense. The innate immune system is our first line of defense against infection, and the induction of cell death can rapidly remove intracellular niches. Inflammasomes are multi-protein signaling complexes that result in pyroptosis, a form of lytic programmed cell death. However, a lack of strong in vivo inflammasome phenotypes has led to the conclusion that inflammasomes merely slow the infection until the adaptive immune system is activated. In Chapter 2, we report that inflammasomes provide penetrating and sterilizing immunity against two ubiquitous environmental bacteria, Chromobacterium violaceum and Burkholderia thailandensis. Additionally, the study of C. violaceum revealed the first evidence of natural killer (NK) cell cytotoxicity in defense against a bacterium in vivo. Thus, environmental microbes are powerful immunological probes and have great potential as model organisms. NK cells and cytotoxic T lymphocytes (CTLs) canonically induce apoptosis in target cells via granzyme B (a serine protease), which can directly cleave and activate caspase-3 and caspase-7. However, caspase-7 is often overlooked because, through the use of specific infectious models, it has been deemed dispensable for defense –an evolutionary relic. It is only expressed in specific tissues (such as the liver and gut) and has never been ascribed a unique and specific role independent of caspase-3. In Chapter 3, we show that caspase-7 is uniquely required for defense against C. violaceum and Listeria monocytogenes. Caspase-3 could not compensate for the loss of caspase-7 in these models, and we demonstrate that caspase-7 activity is dependent upon perforin from either NK cells or CTLs. Furthermore, our results suggest a paradigm in which caspase-7 is preferentially required during bacterial, but not viral, infection. Programmed cell death is a powerful anti-microbial defense. The innate immune system is our first line of defense against infection, and the induction of cell death can rapidly remove intracellular niches. Inflammasomes are multi-protein signaling complexes that result in pyroptosis, a form of lytic programmed cell death. However, a lack of strong in vivo inflammasome phenotypes has led to the conclusion that inflammasomes merely slow the infection until the adaptive immune system is activated. In Chapter 2, we report that inflammasomes provide penetrating and sterilizing immunity against two ubiquitous environmental bacteria, Chromobacterium violaceum and Burkholderia thailandensis. Additionally, the study of C. violaceum revealed the first evidence of natural killer (NK) cell cytotoxicity in defense against a bacterium in vivo. Thus, environmental microbes are powerful immunological probes and have great potential as model organisms. NK cells and cytotoxic T lymphocytes (CTLs) canonically induce apoptosis in target cells via granzyme B (a serine protease), which can directly cleave and activate caspase-3 and caspase-7. However, caspase-7 is often overlooked because, through the use of specific infectious models, it has been deemed dispensable for defense –an evolutionary relic. It is only expressed in specific tissues (such as the liver and gut) and has never been ascribed a unique and specific role independent of caspase-3. In Chapter 3, we show that caspase-7 is uniquely required for defense against C. violaceum and Listeria monocytogenes. Caspase-3 could not compensate for the loss of caspase-7 in these models, and we demonstrate that caspase-7 activity is dependent upon perforin from either NK cells or CTLs. Furthermore, our results suggest a paradigm in which caspase-7 is preferentially required during bacterial, but not viral, infection.
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  • In Copyright
Advisor
  • Miao, Edward
  • Su, Lishan
  • Duncan, Joseph
  • Miller, Virginia
  • Whitmire, Jason
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017
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