Details

Autor(en) / Beteiligte

• Shives, Katherine Delaney

Titel

MTOR complex 1 regulates translation initiation events of (+)-sense RNA viruses

Ort / Verlag

ProQuest Dissertations & Theses

Erscheinungsjahr

2016

Link zum Volltext

• ProQuest

Quelle

ProQuest Dissertations & Theses A&I

Beschreibungen/Notizen

• Since the introduction of West Nile virus in New York City in 1999, West Nile virus (WNV) has spread to all 48 contiguous United States and is now the leading cause of epidemic encephalitis in North America. As member of the family Flaviviridae, WNV is part of a group of clinically-important human pathogens including Dengue virus, Zika virus, and Japanese encephalitis virus. This family of (+)-sense, single stranded RNA viruses have limited coding capacity and are therefore obligated to co-opt cellular factors in order to translate their RNA genomes. Our previous work has shown that WNV growth was independent of macroautophagy activation, but the role of the evolutionarily-conserved mammalian target of rapamycin (mTOR) pathway during WNV infection was not well understood. MTOR is a serine/threonine kinase that acts as a central cellular sensor of nutrient status and exercises control of vital anabolic and catabolic cellular responses such as protein synthesis and autophagy, respectively. We demonstrate herein that WNV activates mTOR complex 1 (mTORC1) and cognate downstream regulators of cap-dependent translation initiation to promote translation of the viral RNA genome. Furthermore, pharmacologic inhibition of these signal transduction pathways or inducible knockout of mTORC1 cofactor Raptor results in a significant WNV growth defect, demonstrating a reliance on host factors that regulate translation initiation. As a final experiment, we also demonstrate here that WNV is indeed dependent on formation of the canonical cap-dependent translation initiation complex eIF4F, as WNV is unable to grow under conditions where eIF4F complex formation is inhibited. Our results suggest that WNV is required to co-op specific host factors that regulate translation in the cell, and that targeting of these key factors may result in future therapeutics for the clinical management of acute flaviviral disease.