Cover
Title Page
Preface
List of Abbreviations
1 The History of ZIKV Discovery
1. 1.1 ZIKV Isolation from Monkeys and Mosquitos
2. 1.2 ZIKV Infection in Humans
3. 1.3 ZIKV Infection Spread to Other Hosts and Regions
4. 1.4 Cross‐Paths between ZIKV and Other Flaviviruses
5. References
2 ZIKV: From Silent to Epidemic
1. 2.1 Outbreak in Yap Island (2007)
2. 2.2 Outbreak in French Polynesia (2013)
3. 2.3 How Did ZIKV Reach Brazil?
4. 2.4 Outbreak in Brazil (2015)
5. 2.5 ZIKV Spread through South, Central, and North Americas
6. References
3 ZIKV Transmission and Prevention
1. 3.1 Modes of Transmission
2. 3.2 Prevention
3. References
4 Association with Guillain‐Barré Syndrome and Microcephaly
1. 4.1 Association with Neurological Disorders
2. References
5 ZIKV Animal Models
1. 5.1 Animal Models: Embryonated Hen Eggs
2. 5.2 Animal Models: Landrace Piglet
3. 5.3 Animal Models: Mice
4. 5.4 Animal Model: Nonhuman Primate
5. References
6 Biology of ZIKV
1. 6.1 Structural and Physical Properties of ZIKV Virion
2. 6.2 Binding and Entry
3. 6.3 Genome Structure
4. 6.4 Translation and Proteolytic Processing
5. 6.5 Features of the Nonstructural Proteins
6. 6.6 RNA Replication
7. 6.7 Features of the Structural Proteins
8. 6.8 Virus Assembly and Release from Virus‐Infected Cells
9. References
7 Zika Virus (ZIKV) Strains and Lineages
1. 7.1 East and West African Lineage
2. 7.2 Africa vs. Asian/American Lineage
3. References
8 ZIKV‐Host Interactions
1. 8.1 Systematic Studies to Identify ZIKV Affected Functions and Pathways
2. 8.2 Induction and Dysregulation of Innate Immune Responses during ZIKV Infection
3. 8.3 Induction of Cell Death and Apoptosis by ZIKV
4. 8.4 Induction of Autophagy by ZIKV
5. 8.5 Dysregulation of Cell Cycle and Induction of Abnormal Mitosis by ZIKV
6. References
9 Inhibitors of ZIKV Replication and Infection
1. 9.1 Drugs That Lead to the Destruction of ZIKV Virions
2. 9.2 Drugs That Inhibit ZIKV Entry and Endocytosis
3. 9.3 Drugs That Target ZIKV NS2B‐NS3 Protease Activity
4. 9.4 Drugs That Target ZIKV NS5 RNA‐Dependent RNA Polymerase Activity
5. 9.5 Neutralizing Antibodies That Target ZIKV Structural Protein
6. 9.6 Drugs That Inhibit ZIKV Infection by Targeting Host Machinery
7. 9.7 Drugs That Show Neuroprotective Activity but Do Not Suppress ZIKV Replication: Emricasan
8. 9.8 Other Drugs That Inhibit ZIKV Infection Identified from a Screening of FDA‐Approved Drugs
9. References
10 Long‐Term Care and Perspectives
1. 10.1 Prenatal Care and Diagnosis of Abnormal Fetus Development
2. 10.2 Long‐Term Care for Patients Affected by ZIKV
3. 10.3 Assistance to Families with Children Affected by ZIKV
4. 10.4 Perspectives
5. References
Index
End User License Agreement

List of Illustrations

Chapter 01
1. 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.
2. 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.
3. 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
1. 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
1. Figure 3.1 Sylvatic and urban cycle involving Aedes ssp. Original figure described CHIKV transmission, which also applies to ZIKV and DENV.
2. 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.
3. 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
1. 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.
2. 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
1. Figure 5.1 ZIKV RNA detection in different tissues extracted from mice infected with ZIKV, including young (closed symbols) and adult mice (open symbols).
2. 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.
3. Figure 5.3 Analysis of ZIKV diversity in different tissues from monkey rhesus. Dotted lines indicate consensus changes.
Chapter 06
1. 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.
2. 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.
3. Figure 6.3 Overview of the ZIKV replication cycle.
4. Figure 6.4 ZIKV polyprotein processing to produce mature peptides.
5. 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.
6. 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.
7. 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).
8. 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’‐^m7G_0pppA₁G₂U₃U₄G₅U₆U₇‐3’) 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.
9. 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.
10. 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).
11. 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.
12. 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.
13. 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
1. 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.
2. 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.
3. 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).
4. 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.
5. 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.
6. 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
1. 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.
2. Figure 8.2 The intrinsic (or mitochondrial) and extrinsic (death receptor) pathways of apoptosis.
3. 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
1. Figure 9.1 Structural formula of epigallocatechin gallate (EGCG).
2. Figure 9.2 Synthesis of N‐(2‐(arylmethylimino)ethyl)‐7‐chloroquinolin‐4‐amine derivatives.
3. Figure 9.3 Synthesis of 2,8‐bis(trifluoromethyl)quinoline derivatives 3, 4, and 5.
4. 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.
5. 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.
6. 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.
7. Figure 9.7 Molecular docking complex of berberine with nonstructural 3 (NS3) protein of Zika virus.
8. 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).
9. Figure 9.9 In vitro activity of ATP analogs. (A) Structural formula of ATP and its analogs. (B) In vitro activity of selected triphosphates.
10. 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.

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
m⁶A	N⁶ 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
PRNT₅₀	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