Zika Virus and Diseases E-Book

Suzane R. da Silva

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 410

Veröffentlichungsjahr: 2018

Beschreibung

Compiles the most current information on the Zika virus and its associated diseases This comprehensive book provides the most up-to-date information for students, medical students, and scientists on Zika virus and its associated diseases. It includes all the information related to the Zika virus since its discovery in 1947; its epidemic outbreak in 2007-2014; how the epidemiology changed in America in 2015-2016; its mode of transmission; how to prevent and treat it; and associated diseases. Zika Virus and Diseases: From Molecular Biology to Epidemiology offers complete and up-to-date coverage in 10 chapters. It presents information from papers that attempted to associate the virus with diseases in Africa until the first animal experiment; discusses its association with Guillain-Barré syndrome and microcephaly; describes the basic mechanisms for Zika (ZIKV) replication, including important differences between Dengue (DENV), West-Nile virus (WNV), and ZIKV; explains the difference between the strains and discusses the pathogenesis of them; covers the papers that showed all the interferences that Zika can cause, and the pathways which can be modified; and more. * The first book since 1947 to put together all the scientific information * Compiles all the information received in the last year about Zika virus * Clearly demonstrates the origin and discovery of the virus Zika Virus and Diseases: From Molecular Biology to Epidemiology will appeal to graduate students, medical students, basic researchers, clinicians in infectious disease, microbiology, and virology, as well as people in related disciplines interested in learning more about this topic.

Leseprobe

Table of Contents

Cover

Title Page

Preface

List of Abbreviations

1 The History of ZIKV Discovery

1.1 ZIKV Isolation from Monkeys and Mosquitos

1.2 ZIKV Infection in Humans

1.3 ZIKV Infection Spread to Other Hosts and Regions

1.4 Cross‐Paths between ZIKV and Other Flaviviruses

References

2 ZIKV: From Silent to Epidemic

2.1 Outbreak in Yap Island (2007)

2.2 Outbreak in French Polynesia (2013)

2.3 How Did ZIKV Reach Brazil?

2.4 Outbreak in Brazil (2015)

2.5 ZIKV Spread through South, Central, and North Americas

References

3 ZIKV Transmission and Prevention

3.1 Modes of Transmission

3.2 Prevention

References

4 Association with Guillain‐Barré Syndrome and Microcephaly

4.1 Association with Neurological Disorders

References

5 ZIKV Animal Models

5.1 Animal Models: Embryonated Hen Eggs

5.2 Animal Models: Landrace Piglet

5.3 Animal Models: Mice

5.4 Animal Model: Nonhuman Primate

References

6 Biology of ZIKV

6.1 Structural and Physical Properties of ZIKV Virion

6.2 Binding and Entry

6.3 Genome Structure

6.4 Translation and Proteolytic Processing

6.5 Features of the Nonstructural Proteins

6.6 RNA Replication

6.7 Features of the Structural Proteins

6.8 Virus Assembly and Release from Virus‐Infected Cells

References

7 Zika Virus (ZIKV) Strains and Lineages

7.1 East and West African Lineage

7.2 Africa vs. Asian/American Lineage

References

8 ZIKV‐Host Interactions

8.1 Systematic Studies to Identify ZIKV Affected Functions and Pathways

8.2 Induction and Dysregulation of Innate Immune Responses during ZIKV Infection

8.3 Induction of Cell Death and Apoptosis by ZIKV

8.4 Induction of Autophagy by ZIKV

8.5 Dysregulation of Cell Cycle and Induction of Abnormal Mitosis by ZIKV

References

9 Inhibitors of ZIKV Replication and Infection

9.1 Drugs That Lead to the Destruction of ZIKV Virions

9.2 Drugs That Inhibit ZIKV Entry and Endocytosis

9.3 Drugs That Target ZIKV NS2B‐NS3 Protease Activity

9.4 Drugs That Target ZIKV NS5 RNA‐Dependent RNA Polymerase Activity

9.5 Neutralizing Antibodies That Target ZIKV Structural Protein

9.6 Drugs That Inhibit ZIKV Infection by Targeting Host Machinery

9.7 Drugs That Show Neuroprotective Activity but Do Not Suppress ZIKV Replication: Emricasan

9.8 Other Drugs That Inhibit ZIKV Infection Identified from a Screening of FDA‐Approved Drugs

References

10 Long‐Term Care and Perspectives

10.1 Prenatal Care and Diagnosis of Abnormal Fetus Development

10.2 Long‐Term Care for Patients Affected by ZIKV

10.3 Assistance to Families with Children Affected by ZIKV

10.4 Perspectives

References

Index

End User License Agreement

List of Tables

Chapter 09

Table 9.1 ZIKV Inhibition and Cytotoxicity Characteristics of Selected Nucleoside Analogues.

Table 9.2 Candidate Anti‐ZIKV Drugs and Considerations for Use in Pregnancy.

List of Illustrations

Chapter 01

Figure 1.1 Alexander J. Haddow in the Zika Forest. The base of the platform used to capture mosquitoes and keep the monkeys can be observed.

Figure 1.2 Details of the steel tower used as a platform to collect mosquitos, and to keep the caged monkeys in the Zika Forest. The platforms can reach the canopy of the trees.

Figure 1.3 Details on the stairs used to access and recover the mosquitoes caught. A boy can be observed in the picture, since they were used to help the researchers to collect the samples in the high height.

Chapter 02

Figure 2.1 Map showing the distribution of ZIKV infection in humans (colorful areas) and animals (sketches) following the chronological outbreaks in different regions.

Chapter 03

Figure 3.1 Sylvatic and urban cycle involving

Aedes ssp

. Original figure described CHIKV transmission, which also applies to ZIKV and DENV.

Figure 3.2 Example of a backyard with containers that will accumulate water in the rainy season, promoting deposition of

Aedes ssp.

eggs in the water.

Figure 3.3 Water accumulated in the plate under the flower vase. This is one of the most common places

Aedes ssp.

deposit their eggs, contributing to ZIKV dissemination.

Chapter 04

Figure 4.1 Illustration of the differences in head circumferences between microcephaly cases and the normal newborns. On December 2015, Brazil classified a newborn as having microcephaly if the head circumference is under or equal to 32 cm.

Figure 4.2 (A, B) Transmission electron micrographs of mock‐infected cells, showing nuclei and organelles with normal aspect after 24 and 72 hours of culture. (C–F) ZIKV‐infected cells 24 hours (C, D), 48 hours (E) and 72 (F) hours after infection. Cells in early (C) and late (F) apoptotic processes. (D) The presence of large perinuclear autophagic vacuoles (AV) can be observed. Black arrows indicate mitochondria with altered morphology. (E) Presence of viral capsid in intracellular vacuole. (G) Immunostaining for ZIKV (green) and the autophagic vacuole marker LC3 (red). Nuclei are stained with DAPI (blue). White arrows indicate cells with negative or low ZIKV staining, and absence of perinuclear LC3 staining. Scale bars = 20 µm.

Chapter 05

Figure 5.1 ZIKV RNA detection in different tissues extracted from mice infected with ZIKV, including young (closed symbols) and adult mice (open symbols).

Figure 5.2 Fetuses from FVB/NJ pregnant female mice (injected with ZIKV at 9.5 days post‐coitus (d.p.c.), and harvested at 16.5 d.p.c.) organized in order of slight to severe malformation (A‐H). Littermates with normal (I‐M) and abnormal (N‐P) phenotypes. The white arrowhead indicates an atypical forelimb posture. Scale bar, 2.0 mm.

Figure 5.3 Analysis of ZIKV diversity in different tissues from monkey rhesus. Dotted lines indicate consensus changes.

Chapter 06

Figure 6.1 Representative phylogram of the genus Flavivirus. The phylogenetic tree was plotted based on complete NS5 nucleotide sequence built from a multiple alignment using Clustal omega and Phylogeny.fr. (235). The scale represents 0.2 substitutions per site. Accession numbers of viral genome sequences are displayed. The arrow highlights ZIKV.

Figure 6.2 The cryo‐EM structure of ZIKV at 3.8 Å. (A) A representative cryo‐EM image of frozen, hydrated ZIKV, with smooth, mature virus particles highlighted with a surrounding black box, and a partially mature virus particle indicated by the yellow arrow. (B) A surface‐shaded depth cued representation of ZIKV. The black triangle indicates the asymmetric unit. (C) A cross‐section view of ZIKV displaying the radial density distribution. Panels B and C are color‐coded based on the radii. Blue: up to 130 Å; cyan: 131 Å to 150 Å; green: 151 Å to 190 Å; yellow: 191 Å to 230 Å, red: from 231 Å. (D) A plot of the Fourier shell coefficient (FSC) showing the reconstruction resolution of 3.8 Å. (E) The Cα backbone of the E and M proteins in the icosahedral ZIKV particle showing the herringbone organization. The orientation is the same as in Panel B. E protein domains are color‐coded based on standard designation. Red: domain I; yellow: domain II; blue: domain III. (F) Representative cryo‐EM electron densities of several amino acids of the E protein.

Figure 6.3 Overview of the ZIKV replication cycle.

Figure 6.4 ZIKV polyprotein processing to produce mature peptides.

Figure 6.5 Structure of ZIKV NS1 dimer. (A) Ribbon diagram of NS1 dimer, with one subunit in gray and the other color‐coded by domain. Green: β‐roll; orange: wing; magenta: connector subdomain; blue: central β‐ladder. N‐linked glycosylation sites are indicated in sticks, and the glycans are shown in spheres. (B) Topology diagram of the NS1 monomer. Color pattern is the same as in Panel A. Glycosylation sites are shown as red hexagons and disulfide bonds as yellow circles. (C) Side views of the NS1 dimer from the wing (left panel) and the end of the β‐ladder (right panel). The β‐roll, connector subdomain, and the intertwined loop (yellow) of the wing domain form a discontinuous protrusion on one face of the β‐ladder with the spaghetti loop (cyan) on the other face. The wing domain is omitted from the left image for clarity. Color pattern is the same as in Panel A.

Figure 6.6 Model of the ZIKV NS1 hexamer. The ZIKV NS1 hexamer is modeled using the full‐length DENV2 NS1 structure (PDB code: 4O6B) (236). Each monomer is color‐coded by domains. Green: β‐roll; orange: wing; magenta: connector subdomain; blue: central β‐ladder. The intertwined loop “spike” of ZIKV NS1 involved membrane association is shown in red and highlighted by dotted lines.

Figure 6.7 The structure of ZIKV NS3 helicase. (A) Size‐exclusion chromatograms of ZIKV helicase. (B) Ribbon diagram of ZIKV helicase structure. (C) A cartoon diagram showing the overall fold with potential RNA binding site and NTPase active site highlighted. (D) Structure‐based phylogenetic tree diagram of eight viral helicases from the Flaviviradae family using the program SHP and PHYLIP (237, 238). The PDB IDs of viral helicase structures are listed as follow: HCV (1HEI), DENV‐2 (2BMF), DENV‐4 (2JLQ), MVEV (2V8O), KUNV (2QEQ), JEV (2Z83), and YFV (1YKS).

Figure 6.8 Structure of ZIKV NS5 methyltransferase domain (MT). (A) Comparison of MT structures of five flaviviruses. The PDB IDs of viral MT structures are listed as follow: DENV (3P97), YFV (3EVC), WNV (2OY0), and JEV (4K6M). SAH or SAM and GTP are shown in sticks. (B) Surface of ZIKV NS5 MT involved in Cap‐0 RNA (5’‐

m7

G

0ppp

A

1

G

2

U

3

U

4

G

5

U

6

U

7

‐3’) binding. Positively and negatively charged surface are colored blue and red, respectively. (C) Surface view of ZIKV NS5 MT with colored active site (magenta), and binding sites for GTP (orange) and SAM (green). (D) Key residues of ZIKV NS5 MT essential for GTP binding (orange), SAM binding (green) and catalysis (magenta). SAH is shown in blue sticks.

Figure 6.9 Structure of full‐length ZIKV NS5. (a) Structure of full‐length ZIKV NS5. A top view look into the active site of the RdRp (left panel) and a side view (right panel) are shown. (b) Schematic representation of ZIKV NS5 showing the locations of key residues and structural motifs. Panel A and B are color‐coded accordingly based on domains and structural motifs. The active site residues of the MT and the RdRp are shown in pink and purple sticks, respectively. The SAH molecule binding to the MT is shown by the magenta stick model.

Figure 6.10 Electron tomography of ZIKV‐induced vesicle packets in hNPCs. (A and B) Electron tomography analysis showing ZIKV‐induced vesicles (Ve) within the rough ER and virions (Vi) in hNPC. hNPCs were fixed at 24 h.p.i., and embedded in epoxy resin for electron tomography analysis. (C) 3D surface model of the boxed area in panel A, showing virus‐induced vesicles (dark gray), virions (white), and intermediate filaments (lines). ER membranes are shown in light blue. (D–F) Slice through the tomogram showing the pore‐like openings (arrowheads) of ZIKV‐induced vesicles toward the cytoplasm. A potential ZIKV budding event (Vi?) on the ER tubule opposing the vesicle pore was observed (F). (G and H) Reconstruction of the areas shown in panel D and E. Arrowheads refer to the vesicle pores marked in panel D and E. Scale bars, 100 nm in (A), (B), and (D–H); 200 nm in (C).

Figure 6.11 Structural aspects of the flavivirus capsid protein. (A) Cartoon of the capsid dimer showing the four alpha helices (α1–α4) in each monomer (PDB ID: 1R6R). Chain A is shown in dark gray and chain B in light gray. Surface representation of each pose is shown on top right. (B) Non‐polar and polar regions of the capsid protein. Hydrophobic clefts are exhibited as transparent surfaces. Arginine residues located in the α4‐α4’ region are represented by the ball‐and‐stick models. (C) Orientation model of the capsid protein during virus assembly.

Figure 6.12 Structure of the ZIKV E protein. (A) Domain organization of ZIKV E protein. ZIKV E protein has three distinct domains: β‐barrel‐shaped domain I, finger‐like domain II, and immunoglobulin‐like domain III. (B) Dimer structure of ZIKV E proteins. Domain II is responsible for the dimerization of E proteins. The fusion loop is buried by the domains I and II of the other E monomer.

Figure 6.13 Structure of the dengue virion and conformations of the E protein. (A) The cryo‐EM reconstruction of the immature virion at neutral pH (239). The E protein forms a heterodimer with prM, and prM‐E heterodimers form 60 trimeric spikes that extend away from the surface of the virus. This arrangement of E represents the initial particle that buds into the ER. In this conformation, the pr peptide (dark gray at the top) protects the fusion peptide (intermediate gray at the center) on E (light gray at the bottom). (B) The cryo‐EM reconstruction of the immature virion at low pH (240). During its transit through the secretory pathway, the virus encounters low pH in the trans‐Golgi network (TGN). The prM‐E heterodimers dissociate and form 90 dimers that lie flat against the viral surface. (C) While in the TGN, the prM protein is cleaved by host endoprotease furin into pr peptide and M protein. The cleaved pr peptide maintains its position as a cap on E, while E proteins remain as 90 homodimers lying parallel to the virion surface. M protein lies embedded in the viral membrane beneath the E protein shell. (D) The cryo‐EM reconstruction of the mature virion (241). Following furin cleavage, the mature virion is secreted into the extracellular milleu and the pr peptide is released from mature particle.

Chapter 07

Figure 7.1 Nucleotide and amino acid alignments for different strains of ZIKV. Neighbor‐joining phylogeny generated from open reading frame nucleotide sequences of ZIKV strains. The tree was rooted with Spondweni virus (DQ859064). The scale at the bottom of the tree represents genetic distance in nucleotide substitutions per site. Numbers at the nodes represent percent bootstrap support values based on 1,000 replicates. Isolates are represented according to strain name, country of origin, and year of isolation. The lineage of each virus is indicated to the right of the tree.

Figure 7.2 Zika virus phylogeny. Nucleotide (top) and amino acid (bottom) sequences of the envelope protein/gene of Zika virus strains showing deletions in the potential glycosylation sites of the MR 766 (Uganda, 1947) and the IbH 30656 (Nigeria, 1968) strains. Deletions are indicated by dashes. The “N” at position 467 of the P6‐740 strain (Malaysia, 1966) represents an equally weighted double population of the nucleotides “C” and “T.” This translates to an “X” at position 165 of the amino acid alignment.

Figure 7.3 Bayesian maximum clade credibility tree generated from coding sequence data. Bayesian posterior probabilities are given at nodes of importance. Isolates implicated in diseases are highlighted. EC_2007 refers to the epidemic consensus sequence generated from the Yap Island outbreak in 2007 (EU545988).

Figure 7.4 Comparison of protein coding region for African and Asian ZIKV lineage. The mean pairwise identity of all pairs at a given position is indicated by the identity bar; light gray denotes 100% pairwise identity, dark gray highlights positions possessing less than 100% pairwise identity. Positions and quantities of amino acid substitutions are indicated by black bands within gray sequence bars. Sequences 1–37, highlighted gray, correspond to the outbreak originating in 2015 in South America.

Figure 7.5 Comparison of the 5’UTR nucleotide sequences of Asian and African ZIKV isolates. The mean pairwise identity of all pairs at a given position is indicated by the identity bar; lilac is indicative of 100% pairwise identity, dark gray highlights positions possessing <100% pairwise identity. Positions and quantities of single nucleotide polymorphisms (SNPs) are represented as black bands within gray sequence bars. Sequences 1–32, highlighted gray, correspond to the outbreak originating in 2015 in Brazil.

Figure 7.6 Comparison of the 3’UTR nucleotide sequences of Asian and African ZIKV isolates. The mean pairwise identity of all pairs at a given position is indicated by the identity bar: light gray is indicative of 100% pairwise identity, dark gray highlights positions possessing less than 100% pairwise identity. Sequences 1–32, highlighted gray, correspond to the outbreak originating in 2015 in Brazil.

Chapter 08

Figure 8.1 RIG‐I‐like receptors (RLRs) serve as cytosolic sensors for viral RNA to initiate anti‐viral and inflammatory cell responses. MDA5 recognizes dsRNA while RIG‐I perceives short ssRNAs or dsRNAs with 5’ triphosphate ends (ppp‐ssRNA). Interaction with viral RNAs recruits downstream effector molecules (e.g., IPS‐1, TRAF 3, and/or STING), thus activating IKK‐related kinases, TBK1, and IKKi. These kinases further induce transcription factors NF‐κB and IRF3/7 to activate transcription of anti‐viral and inflammatory cytokines.

Figure 8.2 The intrinsic (or mitochondrial) and extrinsic (death receptor) pathways of apoptosis.

Figure 8.3 The process of autophagy and formation of autophagosome. (A) The process of autophagy. Cytoplasmic material is initially targeted by phagophore, and then membrane elongates to form an autophagosome. The autophagosome fuses with the lysosome to form an autolysosome, in which the enclosed material is degraded. (B) The molecular events during autophagosome formation. Induction of autophagy leads to the activation of the ULK1. ULK1 forms a complex with Atg13/FIP200/Atg101. The ULK complex translocates to the ER and activates PI3K complex and formation of PI3P phospholipid. The PI3P phospholipid recruits DFCP1 and WIPIs, key factors in autophagosome formation. The subsequent elongation and completion of autophagosome depends on two ubiquitin‐like conjugation pathways, which leads to Atg12‐Atg5‐Atg16L and LC3‐PE complexes. WIPIs and the ATG12‐ATG5‐ATG16L1 complex (outer membrane of the isolation membrane) and LC3‐PE (outer and inner membrane of the isolation membrane) can emerge from subdomains of the ER.

Chapter 09

Figure 9.1 Structural formula of epigallocatechin gallate (EGCG).

Figure 9.2 Synthesis of N‐(2‐(arylmethylimino)ethyl)‐7‐chloroquinolin‐4‐amine derivatives.

Figure 9.3 Synthesis of 2,8‐bis(trifluoromethyl)quinoline derivatives 3, 4, and 5.

Figure 9.4 Crystal structure of eZiPro in complex with the C terminal TGKR tetra‐peptide of NS2B. (A) Full‐length NS2B and NS3 proteins and construct designs of eZiPro, gZiPro, and bZiPro. (B) Overall structure of eZiPro showing the TGKR NS2B peptide bound in substrate binding site. NS2B and NS3 are colored in magenta and yellow, respectively. (C) Interactions between viral peptide and residues from protease. (D) Surface charge density view of NS2B‐NS3 complex. Residues of substrate binding pockets are labeled. (E) A simulated annealing omit map of the TGKR peptide is contoured at 3σ in green mesh. (F) 2mFo‐DFc electron density map contoured at 1σ in blue.

Figure 9.5 Crystal structure of the ZIKV NS2B‐NS3pro monomer in complex with cn‐716. (A) Ribbon diagram of the complex. NS3pro is shown in light gray and NS2B is shown in dark gray, with secondary‐structure elements labeled. The inhibitor cn‐716 is shown in sticks with carbon and boron in light gray and white, respectively. (B) Close‐up view of the substrate‐binding site with cn‐716 embedded in. The surfaces of NS2B and NS3pro are shown in white and gray, respectively. (C) Structural formula of cn‐716. (D) Schematic drawing and (E) Fobs‐Fcalc difference density (2.5σ) for the cyclic diester and its environment in molecule A. (F) Difference density (2.5σ) for the cyclic diester and its environment in molecule B.

Figure 9.6 Structural formula of two Zika NS2B‐NS3pro inhibitors. (A) Chemical structure of p‐Nitrophenyl‐p‐guanidino benzoate. (B) Chemical structure of Qucertin.

Figure 9.7 Molecular docking complex of berberine with nonstructural 3 (NS3) protein of Zika virus.

Figure 9.8 Structural formula of 10 best lead molecules. (A) ZINC53047591, (B) ZINC13510840, (C) ZINC19705600, (D) ZINC19711173, (E) ZINC25634061, (F) ZINC98342354, (G) ZINC02974658, (H) ZINC04086851, (I) ZINC98342344, (J) ZINC02974656, and (K) berberine (ZINC03779067).

Figure 9.9

In vitro

activity of ATP analogs. (A) Structural formula of ATP and its analogs. (B)

In vitro

activity of selected triphosphates.

Figure 9.10 Interactions between ZIKV E protein and antibody 2A10G6. (A) Four polypeptide elements of antibody 2A10G6 surround the domain II tip of ZIKV E protein. Three polypeptide elements from the heavy chain are shown in light gray and one from the light chain is shown in white. (B) The heavy chain of antibody 2A10G6 forms five hydrogen bonds (dashed lines) with the ZIKV E protein.

Guide

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Zika Virus and Diseases

From Molecular Biology to Epidemiology

Suzane Ramos da SilvaFan ChengShou‐Jiang Gao

Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA

This edition first published 2018© 2018 John Wiley & Sons, Inc.

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Preface

Zika virus (ZIKV), a mosquito‐borne flavivirus, is an emerging infectious agent associated with numerous neurological diseases. Discovered in 1947, the virus was silent for almost 60 years until the recent outbreaks in 2003 and 2013 in the Pacific Islands, and in 2015 in South and Central America. While the virus detected in Africa at the time of discovery was only associated with mild fever, rash, and pain, recent ZIKV outbreaks were associated with neurological disorders such as Guillain‐Barré Syndrome in adults and microcephaly in newborns. The dynamic changes in ZIKV‐associated pathology over the years has prompted extensive studies aimed at understanding the differences among the virus lineages (African vs. Asian/American) isolated from different regions with the goal of developing specific therapeutic drugs.

This book will describe the ZIKV story since its discovery in 1947 up to the most updated studies in 2017. We will cover more than 70 years of ZIKV history with details in the discovery, outbreaks, transmission, associated diseases, animal models that have been developed, ZIKV and cell/host interactions, the differences among ZIKV strains, and drugs that have been tested against ZIKV. This book should provide valuable information for both the general public and scientists.

List of Abbreviations

Abbreviations

Full name

2′‐CMA

2′‐C‐methyladenosine

2′‐CMC

2′‐C‐methylcytidine

2′‐CMG

2′‐C‐methylguanosine

2′‐CMU

2′‐C‐methyluridine

2′‐O‐Me

2′‐O ribose methylation

3‐MA

3‐methyladenine

7‐deaza‐2′‐CMA

7‐deaza‐2′‐C‐methyladenosine

7DMA

7‐deaza‐2′‐C‐methyladenosine

aa

amino acid

AEN

apoptosis enhancing nuclease

AIM

absent in melanoma

ALKBH

Alkylation repair homologs

AMPK

5' adenosine monophosphate‐activated protein kinase

Atg

autophagy‐related protein

ATP

adenosine triphosphate

BPTI

bovine pancreatic trypsin inhibitor

BUNV

Bunyamvera virus

C

capsid protein

CCL

Chemokine (C‐C motif) ligand

CCN

cyclin

CD

cluster of differentiation

CDK

cyclin‐dependent kinase

CDKi

CDK inhibitor

CDKN

cyclin dependent kinase inhibitor

CFS

cerebrospinal fluid

CHIKV

chikungunya virus

CM

conditioned medium

C

max

maximum plasma concentrations

CPAP

centrosomal P4.1‐associated protein

CPE

cytopathic effect

CRISPR

Clustered regularly interspaced short palindromic repeats

CXCL

Chemokine (C‐X‐C motif) ligand

CXCR

C‐X‐C motif chemokine receptor

D.P.C.

days post‐coitus

D.P.I.

days post‐infection

DC

dendritic cell

DC‐SIGN

Dendritic cell‐specific intercellular adhesion molecule‐3‐grabbing non‐integrin

DENV

dengue virus

DISC

death‐inducing signaling complex

DNA

deoxyribonucleic acid

dsRNA

double‐stranded RNA

E

envelope protein

EBV

Epstein‐Barr virus

ELISA

enzyme‐linked immunosorbent assay

ELISA

enzyme‐linked immunosorbent assay

ER

endoplasmic reticulum

FDA

Food and Drug Administration

FFU

focus forming units

FLE

fusion loop epitope

FLUAV

influenza A virus

FLUBV

influenza B virus

fNPC

fetal neural progenitor cell

fNSC

fetal NSC

FTO

fat mass and obesity‐associated protein

GEF

guanine nucleotide exchange factor

GM

genetically modified

GO

gene ontology

GTP

guanosine‐5'‐triphosphate

H2AX

H2A histone family, member X

HAEC

human amnion epithelial cell

HC

Hofbauer cell

HCV

hepatitis C virus

hESC

human embryonic stem cell

HI

hemagglutination‐inhibition

hiPSC

human inducible pluripotent stem cell

HIV

human immunodeficiency virus

hNPC

human neural progenitor cell

hnRNP

heterogeneous nuclear ribonucleoprotein

hpi

hour(s) post infection

HSV

herpes simplex virus

I.C.

intracerebrally

I.P.

intraperitoneally

IFIT

IFN‐induced proteins with tetratricopeptide repeats

IFITM

IFN‐inducible transmembrane protein

IFN

interferon

IKK

IκB kinase

IL

interleukin

IP‐10

Interferon gamma‐induced protein 10

IPS

interferon‐promoter stimulator

iPSC

induced pluripotent stem cells

IRF

IFN regulatory factor

ISG

IFN‐stimulated gene

ISRE

IFN‐stimulated responsive element

IUGR

intrauterine growth restriction

JEV

Japanese encephalitis virus

KUNV

Kunjin virus

LC3

microtubule‐associated protein 1A/1B‐light chain 3

LDH

lactate dehydrogenace

LGP2

laboratory of genetics and physiology 2

LGTV

Langat virus

M

membrane protein

m

6

A

N

6

methylation of adenosine

MAVS

Mitochondrial antiviral‐signaling protein

MAYV

Mayaro virus

MBFV

mosquito‐borne flaviviruses virus

MCM

Mauritian cynomolgus macaque

MCP1

monocyte chemoattractant protein‐1

MDA 5

melanoma‐differentiation‐associated gene 5

MDE

mean day of euthanasia

MEF

mouse embryonic fibroblast

METTL

methyltransferase‐like

MHC

major histocompatibility complex

MLD

mucin‐like domain

moDC

monocyte‐derived DC

MOI

multiplicity of infection

MORF

MOZ‐related factor

MOZ

monocytic leukemic zinc‐finger protein

MPA

mycophenolic acid

MR

monkey rhesus

MRI

magnetic resonance imaging

mRNA

messanger RNA

MTase

methyltransferase

mTORC

mammalian target of rapamycin complex

MyD88

myeloid differentiation primary response gene 88

NCX‐NES cells

neocortical NES cells

NES cells

neuroepithelial stem cells

NF‐κB

nuclear factor‐κB

NKV

no known vector

NMR

nuclear magnetic resonance

NPC

neural progenitor cell

NPC

neural progenitor cells

NS

nonstructural protein

NSC

neural stem cell

NTPase

nucleoside triphosphatase

OAS

2'‐5'‐oligoadenylate synthetase

ORF

open reading frame

p.i.

post‐infection

PAMP

pathogen‐associated molecular pattern

PARP

poly‐ADP ribose polymerase

PAS

pre‐autophagosomal structure

PCD

programmed cell death

PCNT

Pericentrin

PE

phosphatidylethanolamine

PFU

plaque‐forming units

PG

phosphatidylglycerol

PHT

primary human trophoblast

PI3K

phosphatidylinositol‐3‐kinase

PKR

protein kinase R

PKA

protein kinase A

PKI

PKA inhibitor

pNGB

p‐nitrophenyl‐p‐guanidino benzoate

PQS

potential quadruplex sequence

prM

the precursor of membrane protein

PRNT

plaque reduction neutralization tests

PRNT

50

50% plaque reduction neutralizing titer

PRR

pattern recognition receptor

PTEN

phosphatase and tensin homolog

PTK

protein tyrosine kinase

qPCR

quantitative polymerase chain reaction

RANTES

regulated on activation, normal T cell expressed and secreted

RdRp

RNA‐dependent RNA polymerase

RF

replicative form

RGC

radial glia cell

RGP

radial glial progenitor

RI

replicative intermediate

RIG‐I

retinoid‐inducible gene I

RLR

RIG‐I‐like receptors

RNA

ribonucleic acid

ROS

reactive oxygen species

RPE cells

retinal pigment epithelial cells

RSAD

radical S‐adenosyl methionine domain containing

RSP

recombinant subviral particle

RTPase

RNA triphosphatase

RT‐PCR

reverse‐transcriptase polymerase chain reaction

RT‐qPCR

quantitative reverse transcription PCR

S.C.

subcutaneously

SAM

S‐adenosyl‐methionine

SARS

severe acute respiratory syndrome

SD

standard deviation

sfRNA

subgenomic flaviviral RNA

SINV

Sindbis virus

SPOV

Spondweni virus

ssRNA

single stranded RNA

STAT

signal transducer and activator of transcription

STING

stimulator of interferon gene

TAM

Tyro3‐Axl‐Mer

TANK

TRAF family member‐associated NF‐κB activator

TBFV

tick‐borne flavivirus

TBK

TANK‐binding kinase

TEM

transmission electron microscopy

TIM

T‐cell immunoglobin and mucin domain

TIR

Toll/interleukin‐1 receptor

TLR

Toll‐like receptor

t

max

duration to achieve C

max

TMD

transmembrane domain

TMEV

Theiler's mouse encephalomyelitis virus

TNF

tumor necrosis factor

TRAF

tumor necrosis factor receptor‐associated factor

TRAIL

TNF‐related apoptosis inducing ligand

TRIF

TIR‐domain‐containing adapter‐inducing interferon‐β

TSC

tuberous sclerosis

ULK1

Unc‐51‐like kinase

UTR

untranslated region

VEEV

Venezuelan equine encephalitis virus

VP

vesicle packet

WDR

WD40 repeat

WNV

West Nile virus

WS

Webster Swiss

xrRNA

Xrn1‐resistent RNA

YF

yellow fever

YFV

yellow fever virus

YTH

YT521‐B homology

YTHDF

YTH N6‐methyladenosine RNA binding protein

ZFYVE

zinc finger FYVE‐type

ZIKV

Zika virus

ZIKV

BR

ZIKV strain isolated in Brazil

γH2AX

phosphorylated histone H2AX

1The History of ZIKV Discovery

1.1 ZIKV Isolation from Monkeys and Mosquitos

Zika virus (ZIKV) was first isolated in April 1947 in a forest named “Ziika” near Lake Victoria in Uganda (1, 2). It is interesting to note that the term Ziika means “overgrowth” in Luganda (the Bantu language of the Baganda people, commonly used in Uganda). The virus was isolated by researchers from The National Institute for Medical Research in London, United Kingdom (G. W. A. Dick), and The Rockefeller Foundation in New York, United States (S. F. Kitchen and A. J. Haddow), as part of collaborative studies with the Yellow Fever Research Institute in Entebbe, Uganda (Figure 1.1) (1, 2).

Figure 1.1 Alexander J. Haddow in the Zika Forest. The base of the platform used to capture mosquitoes and keep the monkeys can be observed.

Obtained from the University of Glasgow (AJ Haddow and University of Glasgow Archives & Special Collections, Papers of AJ Haddow, GB248 DC 068/80/63).

To monitor emerging infections, the investigators commenced studying the sentinel rhesus monkeys in Bwamba, Uganda, in 1946 (Figure 1.2) (1). Zika Forest was chosen because it was well‐known that monkeys in that area had a high immunity to yellow fever virus (YFV) (3–6). Most of the forest was parallel to the Entebbe‐Kampala Road, and the monkeys were kept in cages in the canopy of the trees (1, 7–9).

Figure 1.2 Details of the steel tower used as a platform to collect mosquitos, and to keep the caged monkeys in the Zika Forest. The platforms can reach the canopy of the trees.

Obtained from the University of Glasgow (AJ Haddow and University of Glasgow Archives & Special Collections, Papers of AJ Haddow, GB248 DC 068/80/62).

At that time, six monkey rhesus (MR) were monitored daily for any variation in their body temperature. One of the monkeys, named MR766, presented an increase in temperature on April 18; hence, a blood sample was collected on April 20. MR766 was monitored for more 30 days but no other symptom was detected. The blood sample collected from MR766 was injected subcutaneously (S.C.) into another monkey named MR771, and into Swiss albino mice, intracerebrally (I.C.) and intraperitoneally (I.P.), for further studies. No sign of infection was observed in either MR771 or the mice injected by I.P. for up to 30 days after inoculation. However, the mice injected by I.C. became sick 10 days post‐infection (d.p.i.), and the first ZIKV isolation was obtained from these animals. Since this virus was neutralized by serum taken from monkeys MR766 (on May 20) and MR771 (at 35 d.p.i.) but not by sera from these same monkeys before their exposure to ZIKV, the researchers proved that the virus isolated from the mice was originated from monkey MR766. For this reason, the first ZIKV strain isolated was named MR766. A neutralizing antibody is the antibody that can protect the cells from an infection by neutralizing its biological effect (in this case, infection). In this study, it was used in an assay to determine if the virus detected in one animal was the same as the one isolated from the previous animal (1).

In addition to analyzing and collecting samples from the monkeys, the researches were collecting mosquitos for the YF studies (Figure 1.3). Aedes africanus were among the captured ones in 1948. This mosquito was suspected to be involved in the YFV cycle at that time. From January 5 to January 20, nine lots of mosquitos were acquired, and their samples were processed and injected into mice by I.C. with both unfiltered supernatants and Seitz E.K. filtrates. The second isolation of ZIKV (strain E/1), which was also the first from mosquitos, was from lot E/1/48, captured on January 11–12, with 86 mosquitos (1). All six mice inoculated with the unfiltered sample were inactive at 7 d.p.i. For animals that received the filtrated sample, one died at 6 d.p.i. while other was sick at 14 d.p.i. Those inoculates were also injected S.C. into MR758, which showed no sign of sickness. Based on the results observed with the sick mice, blood samples from MR758 were collected on the 8th, 9th, and 10th d.p.i., which were I.C. injected into six mice. From the first injection, one mouse died at 10 d.p.i. and another two became sick at 19 and 20 d.p.i. From the second group of injection, one died at 13 d.p.i., one was sick at 12 d.p.i., and another one developed paralysis, which was identified as Theiler’s encephalomyelitis (10, 11). Mice injected with samples from the third collection had no symptom. Neutralization tests with serum from MR758 proved that these animals had developed neutralization antibodies to ZIKV strains E/1 and MR766. It was concluded that ZIKV was identical to neither YFV, Dengue virus (DENV), nor Theiler's mouse encephalomyelitis virus (TMEV) (1).

Figure 1.3 Details on the stairs used to access and recover the mosquitoes caught. A boy can be observed in the picture, since they were used to help the researchers to collect the samples in the high height.

Obtained from the University of Glasgow (AJ Haddow and University of Glasgow Archives & Special Collections, Papers of AJ Haddow, GB248 DC 068/80/49).

Dick (1952) observed that the virus isolated from MR766 and mosquitos was well adapted after 90 passages in the mouse brain. Data from studies analyzing adaption and pathogenesis became more reproducible. Among the three ZIKV strains tested (MR766, MR758, and E/1), the virus from MR758 caused more cases of mice that presented with paralysis in early passage than the virus from MR766. With all the strains evaluated, the first sign of infection was roughness of the coat. Infection by I.P. injection in mice older than 2 weeks of age was not as efficient in those of 7 days old. Using a late‐passage virus, no significant difference in the infection was observed between unweaned and 5‐ to 6‐week‐old mice (2).

The virus tropism was examined by analyzing infection in different organs, including brain, kidney, lung, liver, and spleen. The results of the mice inoculated by I.C. indicated that the brain was the main target of ZIKV. While other animals including cotton‐rat and guinea pigs could also be infected with ZIKV, no symptom was observed. On the other hand, rabbits could produce antibodies by 21 d.p.i. Other species of monkeys—including rhesus (6 animals), grivet (13 animals), and redtails (2 animals)—were also infected and analyzed. Circulating antibodies were detected in Grivet 733 and Redtail 1044 after ZIKV infection. Interestingly, Grivet 1019 was naturally infected by ZIKV, but this monkey was captured in Sese Island, which was not in the Zika region. In 1950, among the monkey rhesus used for the YFV research, animal MR801 was naturally positive for ZIKV but the only symptom was minor pyrexia. MR801 was kept in the same platform (number 3) where the strain E/1 was isolated from the captured mosquitoes. Platform number 3 was 0.2 miles from platform number 5 where MR766 was infected (2). Antibodies against ZIKV were not detected in small mammals that were trapped in the forest, indicating that the infection was restricted to monkeys, mosquitos, and human beings at that time (12, 13).

Other ZIKV strains were isolated in 1958 from two different catches of Aedes africanus, consisting of 206 (strain Lunyo V) and 127 (strain Lunyo VI) mosquitoes. The Lunyo V strain caused viral encephalitis, skeletal myositis, and myocarditis in adults and infant mice. The virus was passed through the brain and the heart into infant mice via I.C. or I.P. injections. Some of the mice injected with Lunyo VI were paralyzed. The strains were injected into monkeys MR1059 and MR1063, respectively, and no symptoms of infection were observed (14). ZIKV was further isolated from Aedes luteocephalus in Nigeria (15).

1.2 ZIKV Infection in Humans

The timing of the first ZIKV infection in humans is controversial (16). A paper published by MacNamara in 1954 described its isolation and exploited the possible association between ZIKV infection and jaundice (17). Another study, by Bearcroft in 1956, was on a volunteer that self‐injected with the virus, who precisely described the symptoms following the infection (18). The only problem is that the virus isolated in the first study and used in the second one was not ZIKV but a Spondweni virus (SPOV) (16). MacNamara’s study evaluated an epidemic of jaundice in Nigeria (Afikpo Division, Eastern Nigeria). From a study of three patients, the virus was isolated from a 10‐year‐old female patient who was not jaundiced but had symptoms of fever and headache, and her serological response to ZIKV was low (17).

Bearcroft’s study was done to verify whether there was any association between ZIKV and the development of jaundice. A 34‐year‐old European male volunteer was exposed to the virus isolated by MacNamara (1956). Eighty‐two hours post‐infection (h.p.i.), the only symptom was a headache, followed by malaise and pyrexia in the 2nd and 3rd d.p.i. In the 5th d.p.i., there was a peak in the corporal temperature, accompanied by nausea and vertigo, which was diagnosed as histamine reaction. After 7 days, the volunteer had no sign of infection or jaundice. Mice infected with virus collected from the volunteer, in different periods, developed encephalitis after receiving sera collected at 4 and 6 d.p.i., which were around the peak of pyrexia. Meanwhile, the volunteer was exposed to Aedes aegypti, but the mosquitos were not able to transmit the infection to infant white mice (18).

The first clue that both studies were using SPOV was revealed in a study by Simpson (1964), which was also the first one to describe a natural infection of ZIKV in humans (19). In this paper he mentioned that previous isolations of ZIKV were made in Nigeria (West Africa), and Dr. Delphine Clarke had found out that those viruses were closely related to SPOV, which was named CHUKU strain. Another study in 1968 also pointed out that SPOV virus was isolated in Nigeria, and was wrongly identified as ZIKV (20). Simpson was actually the person who contracted the infection while working together with his team in Uganda. A detailed description of his symptoms following the natural infection was recorded. At the 1 d.p.i., he presented a headache, and by 2 d.p.i., he developed a red rash diffused throughout his face, neck, chest, and arms, without itching, and slight pain in the back and thighs. The rash covered all the limbs, including palms and soles. The fever started at 2 d.p.i., followed by malaise. At 3 d.p.i., the patient had no fever and did not feel sick, and at 5 d.p.i., there was no more rash (19). Actually, this was the first study that documented the presence of a rash on humans infected by ZIKV, one of the most common symptoms of ZIKV infection in today’s patients (21).

The first isolation of ZIKV in Nigeria was reported in 1975 by Moore (1975) in a study describing the isolation of 15 arboviruses between 1964 and 1970 (22). Isolation of ZIKV in Oyo State, Nigeria, was described in 1979. The virus was isolated from two patients, a 2½‐year‐old boy with a mild fever in 1971, and a 10‐year‐old male in 1975, who presented with fever, headache, and pain in the body. This study suggested that ZIKV might be widespread, even if it had been isolated at a low rate. One important point mentioned in this study was that ZIKV infection numbers might be underestimated because of the mild symptoms or misdiagnosis with other arthropod‐borne viral infections (23).

1.3 ZIKV Infection Spread to Other Hosts and Regions

Different serological studies were performed around the 1950s and 1960s and showed that the ZIKV infection had reached other areas in Africa and Asia (24, 25). Serological analysis, based on hemagglutination‐inhibition (HI) tests of other animals, were described in 1977 with samples from 2,428 small mammals and 1,202 birds captured over a five‐year period in Kano Plain, Kenya, close to Lake Victoria. The results revealed the prevalence of ZIKV antibodies as follows:

In small mammals:

– 4.0% (58/1,446) in

Arvicanthus niloticus

– 34.0% in (85/250)

Arvicanthis niloticus

– 3.1% (2/63) in

Crocidura occidentalis

In reptiles:

– 40.0% (4/10) in

Boaedon fuliginosus

– 12.5% (1/8) in

Varanus niloticus

in birds:

– 4.0% (2/49) in

Threskiornis aethiopicus

– 2.7% (1/37) in

Bubulcus ibis

and 50.0% (1/2) in

Philomachus pugnax

In other mammals:

– 0.1% (1/655) in goats

– 0.7% (2/283) in sheep

– 0.6% (8/1361) in cattle living close to irrigated areas

– 0.7% (7/963) in cattle from nonirrigated places (26)

Serological studies with human serum collected for the YFV research indicated that humans from some areas were exposed to ZIKV. There was no detection of ZIKV antibodies in the Zika and Kampala regions, while Bwamba had detection rates of ZIKV antibodies at 28.5% (2/7) in adults and 15.4% (2/13) in children, which were higher than the 9.5% (2/21) detection rate of West Nile antibodies in adults in this region (2). Dick (1952) was careful in his study and suggested that just because there was no evidence of an acute disease in humans caused by ZIKV infection, this did not indicate that ZIKV was not important or might not cause any problem in humans (2).

The detection of antibodies against ZIKV in South‐East Asia was published in 1963, revealing that 75.0% (from 100 samples) of the population living in the Federation of Malayan (currently known as Peninsula of Malaya) was positive, while the presence of neutralization antibodies in the north region such as North Vietnam and Thailand (Bangkok and Chiang Mai) was rare (27). In 1965, ZIKV was detected in different regions of the Angola trough with 31.0% (40/129) and 1.5% (2/129) rates in children in the northwestern region by HI and neutralization tests, respectively, and with 57.7% (71/123) and 21.1% (26/123) rates in adults, respectively, by the same methods. In the southwestern region, 32.8% (20/61) and 21.3% (13/61) of the adults were positive by HI and neutralization tests, respectively, and for the eastern region, 3.5% (2/56) and 1.8% (1/56) of the adults were positive, also using HI and neutralization tests, respectively (28). Results from Kano Plain, Kenya, showed that ZIKV was endemic in 1973, but it was considered at a low level. By analyzing sera from children (ages 4–15+ years old) from schools distributed close to Lake Victoria, ZIKV was detected by HI test in 7.2% (40/559) of the children grouped as 12 years old. Since this was considered a low rate, the other ages were not evaluated (29).

In 1974, a serological study to detect different arboviruses analyzed 1,649 human sera from Portugal and identified four (0.25%) individuals that reacted against ZIKV by the HI test, indicating the silent spread of the virus across the continents (30). In 1979, a serological study analyzed 235 samples from Hong Kong and detected 4.6% (11/235) ZIKV‐positive individuals, which also cross‐reacted with other flaviviruses. Among those who had gender and age information, 12.9% (4/31) females and 8.3% (1/12) males between 21 and 40 years old were positive, while 7.1% (1/14) males older than 41 years old were positive (31).

Interesting results were found at Kainji Lake Basin, Nigeria, in 1980, when ZIKV was detected by HI test, with cases concentrated in young adults and adults. Infection rate was correlated with increased age. Specifically, 9.3% (7/75) of 5‐ to 9‐year‐olds, 22.2% (8/36) of 10‐ to 14‐year‐olds, 46.1% (6/13) of 15‐ to 19‐year‐olds, 71.8% (61/85) of 20‐ to 39‐year‐olds, and 77.3% (68/88) of adults 40 years old and older (32) were positive. The continuous ZIKV detection by the HI test throughout Uganda villages in 1984 indicated that the incidence of ZIKV was not common in the region, with infection rates at 3.7% (1/27) in Tokora, 15.4% (2/13) in Nadip, 3.5% (2/58) in Namalu, and 20.0% (3/15) in other regions (33).

1.4 Cross‐Paths between ZIKV and Other Flaviviruses