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Title: Regulation of Yellow Fever Virus Infection Through A Novel Host MicroRNA Dependent Mechanism
Authors: Kim, David
Advisors: Ploss, Alexander
Department: Molecular Biology
Certificate Program: Global Health and Health Policy Program
Class Year: 2018
Abstract: Yellow fever virus (YFV) is an arthropod-borne virus that infects an estimate of 200,000 people and leads to around 30,000 deaths annually. It is a prototypic member of the Flavivirus genus, which contains other numerous epidemic viruses such as Zika virus (ZIKV), West Nile virus (WNV), and dengue virus (DENV). The life cycle of these viruses is still incompletely understood, especially in how they interact with the human host to induce the diseases. The live-attenuated YFV vaccine strain 17D (YFV-17D) is one of the most effective vaccine ever developed. Given its attenuated characteristic and the absence of highbiocontainment requirements for its manipulation, this virus represents an excellent model to advance our knowledge of the flavivirus life cycle. By performing a genome-scale CRISPR-Cas9 functional screen, the Ploss lab recently identified microRNA-4289 as a potential important regulator of YFV-17D infection in vitro. In this thesis, by preforming gain and loss-of-function experiments, we showed that microRNA-4289 plays indeed a proviral role in YFV-17D life cycle. We identified a putative binding site in the coding region of non-structural protein 1 within the YFV genome, as well as in the genome of DENV serotype 4 and ZIKV, that showed a partial match to the mature sequence of miRNA-4289. Specific three synonymous nucleotide mutations in this putative binding site of the YFV-17D genome impacted viral infection in vitro, hence suggesting that this specific nucleotide region regulates viral infection beyond viral protein function. Overall, this study demonstrates the microRNA-4289 is a host factor of YFV-17D infection and a potential target for the development of antiviral strategies. The outcome of such research could provide significant aid to the ongoing battle against YFV epidemics and uncover new insight into the flavivirus life cycle.
Type of Material: Princeton University Senior Theses
Language: en
Appears in Collections:Molecular Biology, 1954-2023
Global Health and Health Policy Program, 2017-2023

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