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Mohanty Dissertation1.78 MB
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Dissertation
RESPIRATORY SYNCYTIAL VIRUS NS2 PROTEIN AND Z-RNA TRIGGER ZBP1 MEDIATED ACTIVATION OF RIPK3-MLKL PATHWAY FOR NLRP3 INFLAMMASOME ACTIVATION
Washington State University
Doctor of Philosophy (PhD), Washington State University
05/2024
DOI:
https://doi.org/10.7273/000007069
Abstract
Respiratory Syncytial Virus (RSV) is the major cause of airway diseases in infants, the elderly, and immunocompromised individuals worldwide. The virus infects the upper and lower airway causing inflammation, cell damage, and airway obstruction, which can lead to long-term complications and death. Regulated inflammation is required for virus clearance, however, exaggerated inflammation results in excessive production of cytokines and chemokines, which can lead to the development of inflammatory diseases like pneumonia and bronchiolitis. Macrophages play a critical role in RSV-associated disease pathogenesis. In macrophages, NLRP3 inflammasome complex constitutes an important innate immune platform involved in induction of pyroptotic lytic cell death and pro-inflammatory response. NLRP3 inflammasome formation results in cleavage of pro-caspase-1 to active form of caspase-1, which then cleaves pro- IL-1β into mature bioactive IL-1β. Active caspase-1 also cleaves Gasdermin D (GSDMD) to release N-terminal domain of GSDMD (NT-GSDMD) for forming pores on plasma membrane to trigger lytic cell death via pyroptosis. IL-1β plays a vital role in enhancing inflammatory responses during RSV infection. Likewise, pyroptosis also contributes to exaggerated inflammation during RSV infection. In the current study, we have identified ZBP1(Z-conformation nucleic acid binding protein 1) as a cytoplasmic Pattern Recognition Receptor (PRR) involved in activation of NLRP3inflammasome in RSV infected macrophages. ZBP1 activated RIPK3-MLKL pathway to activate inflammasome during RSV infection, which resulted in generation of mature IL-1β for pro-inflammatory response and NT-GSDMD for pyroptosis. This process is mediated by two viral encoded Pattern Associated Molecular Patterns (PAMPs), RSV non-structural NS2 protein and Z-RNA. These PAMPs interact with ZBP1 to activate RIPK3-MLKL pathway for inflammasome activation.
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Details
- Title
- RESPIRATORY SYNCYTIAL VIRUS NS2 PROTEIN AND Z-RNA TRIGGER ZBP1 MEDIATED ACTIVATION OF RIPK3-MLKL PATHWAY FOR NLRP3 INFLAMMASOME ACTIVATION
- Creators
- Indira Priyadarsini Mohanty
- Contributors
- Santanu Bose (Chair)Anthony V. Nicola (Committee Member)Troy Bankhead (Committee Member)Tanya Miura (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 129
- Identifiers
- 99901158334901842
- Language
- English
- Resource Type
- Dissertation