Critical Roles of Inflammasome Components NLRs, PYCARD, and Caspase-1 in Host - Pathogen Interactions

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  • June 7, 2019
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  • Huang, Max Tze-Han
    • Affiliation: School of Dentistry, Oral and Craniofacial Biomedicine PhD Program
Abstract
  • The sensors of innate immune defense are indispensible in the fight against foreign and self insults. Three classes of pattern recognition receptors (PRRs) including Toll-like receptors (TLRs), nucleotide binding domain leucine-rich repeat containing receptors (NLRs) and RIG-I-like RNA helicases (RLHs) are designed to recognize conserved microbial moieties called pathogen associated molecular patterns (PAMPs). Recent discoveries on the understanding of the functions of NLRs have advanced our knowledge of how intracellular pathogens are detected and the subsequent host cell mediated immunity. At least four members of the NLR family can form multi-protein complexes termed inflammasomes and initiate downstream functions such as IL-1β/IL-18 processing and cell death execution. In this dissertation, the roles of NLRs and their interacting partners in combating Porphyromonas gingivalis and Francisella tularensis and how these pathogens target host signaling pathways to overcome host defense were examined. In part I, we showed in the absence of NLRP3, PYCARD/ASC or Caspase-1, human monocytic THP-1 cells are unable to release IL-1β when confronted with P. gingivalis. P. gingivalis also induces necrotic like cell death in THP-1 cells and this process requires NLRP3 and PYCARD. In part II, we showed that Francisella tularensis suppresses host immune cytokine release of IL-1β and TNF-α. RipA, a F. tularensis membrane protein, is critical in this process. F. tularensis (Live Vaccine Strain) LVS ripA deletion mutant (LVSΔripA) fails to suppress the release of IL-1β and TNF-α. We showed that LVS activates host signaling pathways including inflammasomes and MAP Kinases and ripA is critical in these processes. Furthermore, the absence of ripA in LVS allows a robust immune responses against this organism in vivo. Taken together, the works in this dissertation demonstrated, for the first time, that NLRs play a critical role in cell mediated host defense against P. gingivalis and elucidated a mechanism by which F. tularenesis targets and suppresses host immune response in the release of pro-inflammatory cytokines.
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  • ... n partial fulfillment of the requirements for the degree of Doctor of Philosophy in the program of Oral Biology.
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  • Ting, Jenny P.-Y.
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