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Host Cell Responses to Zika Virus Infection
Abstract
The re-emergence of Zika virus (ZIKV) in 2015 as a significant human pathogen causing neurological diseases in infants as well as adults is a serious global health concern. A clear understanding of the mechanisms involved in ZIKV replication in infected host cells as well as the host responses to virus infection are keys to the development of therapeutic strategies against ZIKV. Studies conducted in this dissertation demonstrate that ZIKV infection induces the activation of mTOR signaling cascade that promotes viral protein accumulation and infectious progeny production. While both mTORC1 and mTORC2 are essential for ZIKV replication, the observation that depletion of Raptor, the unique component of mTORC1, imposes a robust negative effect on ZIKV protein expression and progeny production also suggests a mTOR- independent role played by Raptor. Additionally, the activation of autophagy at early times of infection indicates an antiviral role for autophagy in ZIKV infection. The observation that pharmacological inhibition of autophagy led to increased accumulation of ZIKV proteins further strengthens this contention. Since infection-induced oxidative stress contributes to ZIKV pathogenesis, studies reported in this dissertation also show that ZIKV infection alters the redox homeostasis in infected cells and triggers Nrf2- mediated antioxidant response. Depletion of Nrf2 downregulates the cellular pool of GSHand NADPH leading to enhanced ZIKV replication thereby underscores a role for cellular antioxidants in the suppression of ZIKV replication. The dependency of ZIKV replication on host cell glycolysis is highlighted by significant reduction in viral protein expression and virus yield due to pharmacologic inhibition. When glycolysis is inhibited, gluconeogenesis was found to facilitate ZIKV replication by compensating carbon input via oxidative mitochondrial metabolism. Further experimentation comparing the metabolic profiles of mock- and ZIKV-infected cells may provide important information in understanding the role of cellular metabolism in virus replication.
Subject Area
Virology
Recommended Citation
Sahoo, Bikash Ranjan, "Host Cell Responses to Zika Virus Infection" (2021). ETD collection for University of Nebraska-Lincoln. AAI28713361.
https://digitalcommons.unl.edu/dissertations/AAI28713361