Coordination of Zika Virus Infection and Viroplasm Organization by Microtubules and Microtubule-Organizing Centers.

Rebecca A Buchwalter,Hengli Tang,Chunfeng Zheng,Christy Hammack,Yichen Cheng,David G Meckes,Sarah C Ogden,Allaura S Cone,Li Sun,Jieyan V Chen,Timothy L Megraw,Sara B York

doi:10.3390/cells10123335

Abstract

Zika virus (ZIKV) became a global health concern in 2016 due to its links to congenital microcephaly and other birth defects. Flaviviruses, including ZIKV, reorganize the endoplasmic reticulum (ER) to form a viroplasm, a compartment where virus particles are assembled. Microtubules (MTs) and microtubule-organizing centers (MTOCs) coordinate structural and trafficking functions in the cell, and MTs also support replication of flaviviruses. Here we investigated the roles of MTs and the cell’s MTOCs on ZIKV viroplasm organization and virus production. We show that a toroidal-shaped viroplasm forms upon ZIKV infection, and MTs are organized at the viroplasm core and surrounding the viroplasm. We show that MTs are necessary for viroplasm organization and impact infectious virus production. In addition, the centrosome and the Golgi MTOC are closely associated with the viroplasm, and the centrosome coordinates the organization of the ZIKV viroplasm toroidal structure. Surprisingly, viroplasm formation and virus production are not significantly impaired when infected cells have no centrosomes and impaired Golgi MTOC, and we show that MTs are anchored to the viroplasm surface in these cells. We propose that the viroplasm is a site of MT organization, and the MTs organized at the viroplasm are sufficient for efficient virus production.

Highlights

First isolated from monkeys in the Zika forest of Uganda in 1947, Zika virus (ZIKV)is a mosquito-borne flavivirus, a genus of positive-sense single-stranded enveloped RNA viruses that include dengue (DENV), yellow fever, and West Nile viruses
We detected changes to the endoplasmic reticulum (ER) morphology during ZIKV infection at 12 h p.i., in which the ER is still distributed around the nucleus but is more compact in infected cells compared with mock-infected cells (Figure 1a–c,h and Figure S1b)
Because viroplasm organization and the localization of ZIKV proteins and double-stranded RNA (dsRNA) is disrupted by MT disassembly, we further examined the effect of noc on virus production

Summary

Introduction

First isolated from monkeys in the Zika forest of Uganda in 1947, Zika virus (ZIKV)is a mosquito-borne flavivirus, a genus of positive-sense single-stranded enveloped RNA viruses that include dengue (DENV), yellow fever, and West Nile viruses. Human transmission for ZIKV was rare until outbreaks occurred in Yap, Micronesia (2007), and French. The 2015–2016 outbreak in the Americas, especially in Brazil, caused global health concern due to the associated microcephaly and additional birth defects collectively known as congenital ZIKV syndrome in newborns of infected pregnant women [1,2]. ZIKV infection impacts cells involved in fetal brain development; ZIKV RNA has been detected in human fetal brain tissue and placenta, and in vitro, ZIKV can infect placental and neuronal cells including neural progenitor cells [2,3,4,5]. The genomes of ZIKV and other flaviviruses encode three structural and seven nonstructural (NS) proteins.

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