Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120 Heidelberg, Germany
Charlotta Funaya
Electron Microscopy Core Facility, Heidelberg University, 69120 Heidelberg, Germany
Nicole Schieber
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
Paolo Ronchi
Electron Microscopy Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
Martin Schorb
Electron Microscopy Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
Priit Pruunsild
Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, 69120 Heidelberg, Germany
Yannick Schwab
Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany; Electron Microscopy Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
Laurent Chatel-Chaix
Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120 Heidelberg, Germany; Institut National de la Recherche Scientifique, Institut Armand-Frappier, Québec H7V 1B7, Canada
Alessia Ruggieri
Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120 Heidelberg, Germany
Ralf Bartenschlager
Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120 Heidelberg, Germany; German Center for Infection Research (DZIF), Heidelberg University, 69120 Heidelberg, Germany; Corresponding author
Summary: A 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. : Cortese et al. show that ZIKV infection in both human hepatoma and neuronal progenitor cells induces drastic structural modification of the cellular architecture. Microtubules and intermediate filaments surround the viral replication factory composed of vesicles corresponding to ER membrane invagination toward the ER lumen. Importantly, alteration of microtubule flexibility impairs ZIKV replication. Keywords: Zika virus, flavivirus, human neural progenitor cells, replication factories, replication organelles, microtubules, intermediate filaments, electron microscopy, electron tomography, live-cell imaging
