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      Zika Fetal Neuropathogenesis: Etiology of a Viral Syndrome

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          Abstract

          The ongoing Zika virus epidemic in the Americas and the observed association with both fetal abnormalities (primary microcephaly) and adult autoimmune pathology (Guillain–Barré syndrome) has brought attention to this neglected pathogen. While initial case studies generated significant interest in the Zika virus outbreak, larger prospective epidemiology and basic virology studies examining the mechanisms of Zika viral infection and associated pathophysiology are only now starting to be published. In this review, we analyze Zika fetal neuropathogenesis from a comparative pathology perspective, using the historic metaphor of “TORCH” viral pathogenesis to provide context. By drawing parallels to other viral infections of the fetus, we identify common themes and mechanisms that may illuminate the observed pathology. The existing data on the susceptibility of various cells to both Zika and other flavivirus infections are summarized. Finally, we highlight relevant aspects of the known molecular mechanisms of flavivirus replication.

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          Most cited references159

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          Composition and Three-Dimensional Architecture of the Dengue Virus Replication and Assembly Sites

          Summary Positive-strand RNA viruses are known to rearrange cellular membranes to facilitate viral genome replication. The biogenesis and three-dimensional organization of these membranes and the link between replication and virus assembly sites is not fully clear. Using electron microscopy, we find Dengue virus (DENV)-induced vesicles, convoluted membranes, and virus particles to be endoplasmic reticulum (ER)-derived, and we detect double-stranded RNA, a presumed marker of RNA replication, inside virus-induced vesicles. Electron tomography (ET) shows DENV-induced membrane structures to be part of one ER-derived network. Furthermore, ET reveals vesicle pores that could enable release of newly synthesized viral RNA and reveals budding of DENV particles on ER membranes directly apposed to vesicle pores. Thus, DENV modifies ER membrane structure to promote replication and efficient encapsidation of the genome into progeny virus. This architecture of DENV replication and assembly sites could explain the coordination of distinct steps of the flavivirus replication cycle.
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            Stress granules: the Tao of RNA triage.

            Cytoplasmic RNA structures such as stress granules (SGs) and processing bodies (PBs) are functional byproducts of mRNA metabolism, sharing substrate mRNA, dynamic properties and many proteins, but also housing separate components and performing independent functions. Each can exist independently, but when coordinately induced they are often tethered together in a cytosolic dance. Although both self-assemble in response to stress-induced perturbations in translation, several recent reports reveal novel proteins and RNAs that are components of these structures but also perform other cellular functions. Proteins that mediate splicing, transcription, adhesion, signaling and development are all integrated with SG and PB assembly. Thus, these ephemeral bodies represent more than just the dynamic sorting of mRNA between translation and decay.
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              Modification of intracellular membrane structures for virus replication

              Key Points Plus-stranded RNA viruses induce large membrane structures that might support the replication of their genomes. Similarly, cytoplasmic replication of poxviruses (large DNA viruses) occurs in associated membranes. These membranes originate from the endoplasmic reticulum (ER) or endosomes. Membrane vesicles that support viral replication are induced by a number of RNA viruses. Similarly, the poxvirus replication site is surrounded by a double-membraned cisterna that is derived from the ER. Analogies to autophagy have been proposed since the finding that autophagy cellular processes involve the formation of double-membrane vesicles. However, molecular evidence to support this hypothesis is lacking. Membrane association of the viral replication complex is mediated by the presence of one or more viral proteins that contain sequences which associate with, or integrate into, membranes. Replication-competent membranes might contain viral or cellular proteins that contain amphipathic helices, which could mediate the membrane bending that is required to form spherical vesicles. Whereas poxvirus DNA replication occurs inside the ER-enclosed site, for most RNA viruses the topology of replication is not clear. Preliminary results for some RNA viruses suggest that their replication could also occur inside double-membrane vesicles. We speculate that cytoplasmic replication might occur inside sites that are 'enwrapped' by an ER-derived cisterna, and that these cisternae are open to the cytoplasm. Thus, RNA and DNA viruses could use a common mechanism for replication that involves membrane wrapping by cellular cisternal membranes. We propose that three-dimensional analyses using high-resolution electron-microscopy techniques could be useful for addressing this issue. High-throughput small-interfering-RNA screens should also shed light on molecular requirements for virus-induced membrane modifications.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                25 August 2016
                August 2016
                : 10
                : 8
                : e0004877
                Affiliations
                [1 ]Department of Biological Sciences, University of the Sciences, Philadelphia, Pennsylvania, United States of America
                [2 ]Department of Bioinformatics and Genomics, University of North Carolina at Charlotte, Charlotte, North Carolina, United States of America
                [3 ]Department of Medicine, Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America
                [4 ]Zika Foundation, College Station, Texas, United States of America
                [5 ]Atheric Pharmaceutical, Scottsville, Virginia, United States of America
                [6 ]Global Clinical Scholars Research Training Program, Harvard Medical School, Boston, Massachusetts, United States of America
                Molecular Biology Unit (MBU), INDIA
                Author notes

                I have read the journal's policy and the authors of this manuscript have the following competing interests: Drs. Robert Malone and Jill Glasspool-Malone are principal stockholders of Atheric Pharmaceutical, LLC. Robert Malone is the managing partner of Atheric Pharmaceutical. Dr. Michael Callahan is the Chief Medical Officer of the Zika Foundation.

                Author information
                http://orcid.org/0000-0003-0340-7490
                Article
                PNTD-D-16-00769
                10.1371/journal.pntd.0004877
                4999274
                27560129
                b7850c5f-43e7-4331-974c-212a6f268861
                © 2016 Klase et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Page count
                Figures: 2, Tables: 2, Pages: 32
                Funding
                The authors received no specific funding for this work. Research reported in this publication was supported by a UNC Research Opportunities Initiative grant to UNC Charlotte, NC State University, and UNC-Chapel Hill. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Review
                Biology and life sciences
                Organisms
                Viruses
                RNA viruses
                Flaviviruses
                Zika Virus
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Viral Pathogens
                Flaviviruses
                Zika Virus
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Viral Pathogens
                Flaviviruses
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                Developmental Biology
                Embryology
                Placenta
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                Nervous System
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                Microcephaly
                Biology and Life Sciences
                Developmental Biology
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