Ultrastructural Characterization of Zika Virus Replication Factories

Mirko Cortese,Sarah Goellner,Eliana Gisela Acosta,Christopher John Neufeldt,Olga Oleksiuk,Marko Lampe,Uta Haselmann,Charlotta Funaya,Nicole Schieber,Paolo Ronchi,Martin Schorb,Priit Pruunsild,Yannick Schwab,Laurent Chatel-Chaix,Alessia Ruggieri,Ralf Bartenschlager

doi:10.1016/j.celrep.2017.02.014

Mirko Cortese, Sarah Goellner + Show 14 more

Open Access

https://doi.org/10.1016/j.celrep.2017.02.014

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Abstract

SummaryA global concern has emerged with the pandemic spread of Zika virus (ZIKV) infections that can cause severe neurological symptoms in adults and newborns. ZIKV is a positive-strand RNA virus replicating in virus-induced membranous replication factories (RFs). Here we used various imaging techniques to investigate the ultrastructural details of ZIKV RFs and their relationship with host cell organelles. Analyses of human hepatic cells and neural progenitor cells infected with ZIKV revealed endoplasmic reticulum (ER) membrane invaginations containing pore-like openings toward the cytosol, reminiscent to RFs in Dengue virus-infected cells. Both the MR766 African strain and the H/PF/2013 Asian strain, the latter linked to neurological diseases, induce RFs of similar architecture. Importantly, ZIKV infection causes a drastic reorganization of microtubules and intermediate filaments forming cage-like structures surrounding the viral RF. Consistently, ZIKV replication is suppressed by cytoskeleton-targeting drugs. Thus, ZIKV RFs are tightly linked to rearrangements of the host cell cytoskeleton.

Highlights

The pandemic outbreak of Zika virus (ZIKV), a member of the Flavivirus genus within the Flaviviridae family, and the association of ZIKV infections with severe disease raised intense concerns
Using Huh7 human hepatic cells and human NPCs (hNPCs), a physiologically relevant target cell of ZIKV, we demonstrate that independent of the lineage, ZIKV induces a drastic reorganization of intermediate filament and microtubule networks and reorganizes the endoplasmic reticulum (ER) to form vesicle packets (VPs), zippered ER, and convoluted membranes (CMs)
ZIKV Replication Depends on the Rearrangement of the Cytoskeletal Network With the aim to study the reorganization of subcellular structures by ZIKV, we first determined the replication kinetics of two virus strains: the historical African strain MR766 and the contemporary Asian strain H/PF/2013

Summary

Introduction

The pandemic outbreak of Zika virus (ZIKV), a member of the Flavivirus genus within the Flaviviridae family, and the association of ZIKV infections with severe disease raised intense concerns. Infection of pregnant women with ZIKV can lead to congenital transmission and eventually to severe microcephaly in newborns (Pierson and Graham, 2016). Intensive efforts have been undertaken to control this emerging disease, but neither antiviral therapies nor a prophylactic vaccine for ZIKV are currently available (Pierson and Graham, 2016). This unmet medical need is exacerbated by the spread of the Aedes mosquito vector beyond tropical countries

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