Zika virus (ZIKV) belongs to the Flavivirus genus of the Flaviviridae family. It is an enveloped RNA virus that enters host cells via receptor-mediated endocytosis. The interactions between viral proteins and particular receptors on the host cell surface is the initial step of the virus life cycle, which represents the key targets for antiviral therapeutic.
Materials and Methods:
This review highlights a variety of cell types infected by ZIKV, including human radial glial cells, endothelial cells, neural progenitor cells, astrocytes, microglia, and Sertoli cells. The cellular molecules involved in the entry process of ZIKV are detailed, and the advances in the development of chemical compounds and neutralizing antibodies targeting the ZIKV entry process are described.
Results:
The interactions of ZIKV with cellular molecules in various host cells during virus entry are reviewed, as the targets of the development of antiviral therapeutics.
Conclusion:
The entry of ZIKV into host cells involves complicated mechanisms, which remain to be further explored to facilitate the development of antiviral reagents.
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References
1.
AlbulescuIC, KovacikovaK, TasA, et al.Suramin inhibits Zika virus replication by interfering with virus attachment and release of infectious particles. Antiviral Res, 2017; 143:230–236.
2.
AraiY, PulversJN, HaffnerC, et al.Neural stem and progenitor cells shorten S-phase on commitment to neuron production. Nat Commun, 2011; 2:154.
3.
ArispeN, DohM, De MaioA. Lipid interaction differentiates the constitutive and stress-induced heat shock proteins Hsc70 and Hsp70. Cell Stress Chaper, 2002; 7(4):330–338.
4.
AseaA, RehliM, KabinguE, et al.Novel signal transduction pathway utilized by extracellular HSP70: Role of toll-like receptor (TLR) 2 and TLR4. J Biol Chem, 2002; 277(17):15028–15034.
5.
Barba-SpaethG, DejnirattisaiW, RouvinskiA, et al.Structural basis of potent Zika-dengue virus antibody cross-neutralization. Nature, 2016; 536(7614):48–53.
6.
BarrowsNJ, CamposRK, PowellST, et al.A screen of FDA-approved drugs for inhibitors of zika virus infection. Cell Host Microbe, 2016; 20(2):259–270.
7.
BerthetN, NakounéE, KamgangB, et al.Molecular characterization of three Zika flaviviruses obtained from sylvatic mosquitoes in the Central African Republic. Vector Borne and Zoonotic Diseases (Larchmont, NY), 2014; 14(12):862–865.
8.
CaoB, ParnellLA, DiamondMS, MysorekarIU. Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice. J Exp Med, 2017; 214(8):2303–2313.
9.
CarneiroBM, BatistaMN, BragaACS, et al.The green tea molecule EGCG inhibits Zika virus entry. Virology, 2016; 496:215–218.
10.
ChavaliPL, StojicL, MeredithLW, et al.Neurodevelopmental protein Musashi-1 interacts with the Zika genome and promotes viral replication. Science, 2017; 357(6346):83–88.
11.
ChenJ, YangY-F, YangY, et al.AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling. Nat Microbiol, 2018; 3(3):302–309.
12.
ChoiH, YangSW, JooJS, et al.Sialylated IVIg binding to DC-SIGN plus Hofbauer cells induces immune tolerance through the caveolin-1/NF-kB pathway and IL-10 secretion. Clin Immunol, 2023:246.
13.
CoanPM, Ferguson-SmithAC, BurtonGJ. Ultrastructural changes in the interhaemal membrane and junctional zone of the murine chorioallantoic placenta across gestation. J Anat, 2005; 207(6):783–796.
14.
DaiL, SongJ, LuX, et al.Structures of the Zika virus envelope protein and its complex with a flavivirus broadly protective antibody. Cell Host Microbe, 2016; 19(5):696–704.
15.
DavisCW, NguyenHY, HannaSL, et al.West Nile virus discriminates between DC-SIGN and DC-SIGNR for cellular attachment and infection. J Virol, 2006; 80(3):1290–1301.
16.
DelvecchioR, HigaLM, PezzutoP, et al.Chloroquine, an endocytosis blocking agent, inhibits Zika virus infection in different cell models. Viruses, 2016; 8(12).
17.
DengY-Q, DaiJ-X, JiG-H, et al.A broadly flavivirus cross-neutralizing monoclonal antibody that recognizes a novel epitope within the fusion loop of E protein. PLoS One, 2011; 6(1):e16059.
18.
DengYQ, ZhangNN, LiCF, et al.Adenosine Analog NITD008 Is a Potent Inhibitor of Zika Virus. Open Forum Infect Dis, 2016; 3(4):ofw175.
19.
DickGWA, KitchenSF, HaddowAJ. Zika Virus (I). Isolations and serological specificity. Trans R Soc Trop Med Hyg, 1952; 46(5):509–520.
20.
DiopF, VialT, FerrarisP, et al.Zika virus infection modulates the metabolomic profile of microglial cells. PLoS One, 2018; 13(10):e0206093.
21.
DitlevsenDK, KolkovaK. Signaling pathways involved in NCAM-induced neurite outgrowth. Structure and Function of the Neural Cell Adhesion Molecule NCAM, 2010; 663:151–168.
22.
DuffyMR, ChenT-H, HancockWT, et al.Zika virus outbreak on Yap Island, Federated States of Micronesia. N Engl J Med, 2009; 360(24):2536–2543.
23.
EderJ, Zijlstra-WillemsE, KoenG, et al.Transmission of Zika virus by dendritic cell subsets in skin and vaginal mucosa. Front Immunol, 2023; 14:1125565.
24.
EngeringA, GeijtenbeekTBH, van VlietSJ, et al.The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. Journal of Immunology (Baltimore, Md: 1950), 2002; 168(5):2118–2126.
25.
FernandoS, FernandoT, StefanikM, et al.An approach for Zika virus inhibition using homology structure of the envelope protein. Mol Biotechnol, 2016; 58(12):801–806.
26.
FerreiraAC, Zaverucha-do-ValleC, ReisPA, et al.Sofosbuvir protects Zika virus-infected mice from mortality, preventing short- and long-term sequelae. Sci Rep, 2017; 7(1):9409.
27.
FinkSL, VojtechL, WagonerJ, et al.The antiviral drug arbidol inhibits the zika virus. Sci Rep, 2018; 8(1):8989.
28.
FraAM, WilliamsonE, SimonsK, PartonRG. De novo formation of caveolae in lymphocytes by expression of VIP21-caveolin. Proc National Academy of Sciences of the United States of America, 1995; 92(19):8655–8659.
29.
GarcezPP, LoiolaEC, Madeiro da CostaR, et al.Zika virus impairs growth in human neurospheres and brain organoids. Science, 2016; 352(6287):816–818.
30.
GeijtenbeekTB, TorensmaR, van VlietSJ, et al.Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell, 2000; 100(5):575–585.
31.
GoveroJ, EsakkyP, ScheafferSM, et al.Zika virus infection damages the testes in mice. Nature, 2016; 540(7633):438–442.
32.
HaDP, LeeAS. Insulin-like growth factor 1-receptor signaling stimulates GRP78 expression through the PI3K/AKT/mTOR/ATF4 axis. Cell Signal, 2020; 75:109736.
33.
HamelR, DejarnacO, WichitS, et al.Biology of Zika virus infection in human skin cells. J Virol, 2015; 89(17):8880–8896.
34.
HastingsAK, YockeyLJ, JaggerBW, et al.TAM receptors are not required for Zika virus infection in mice. Cell Rep, 2017; 19(3):558–568.
35.
HulinaA, RajkovicMG, DespotDJ, et al.Extracellular Hsp70 induces inflammation and modulates LPS/LTA-stimulated inflammatory response in THP-1 cells. Cell Stress Chaperones, 2018; 23(3):373–384.
36.
JulanderJG, SiddharthanV, EvansJ, et al.Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model. Antiviral Res, 2017; 137:14–22.
37.
KamiyamaN, SomaR, HidanoS, et al.Ribavirin inhibits Zika virus (ZIKV) replication in vitro and suppresses viremia in ZIKV-infected STAT1-deficient mice. Antiviral Res, 2017; 146:1–11.
38.
KariolisMS, MiaoYR, JonesDS, et al.An engineered Axl ‘decoy receptor’ effectively silences the Gas6-Axl signaling axis. Nat Chem Biol, 2014; 10(11):977–983.
39.
KhongwichitS, SornjaiW, JitobaomK, et al.A functional interaction between GRP78 and Zika virus E protein. Sci Rep, 2021; 11(1):393.
40.
KimSY, ZhaoJ, LiuX, et al.Interaction of Zika virus envelope protein with glycosaminoglycans. Biochemistry, 2017; 56(8):1151–1162.
41.
KleeneR, MzoughiM, JoshiG, et al.NCAM-induced neurite outgrowth depends on binding of calmodulin to NCAM and on nuclear import of NCAM and fak fragments. J Neurosci, 2010; 30(32):10784–10798.
42.
KumarA, HouS, AiroAM, et al.Zika virus inhibits type-I interferon production and downstream signaling. EMBO Rep, 2016; 17(12):1766–1775.
43.
KumarA, JovelJ, Lopez-OrozcoJ, et al.Human Sertoli cells support high levels of Zika virus replication and persistence. Sci Rep, 2018; 8(1):5477.
44.
LadnerJT, WileyMR, PrietoK, et al.Complete genome sequences of five Zika virus isolates. Genome Announc, 2016; 4(3); doi: 10.1128/genomea.00377-16
45.
LiZ, BrecherM, DengY-Q, et al.Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction. Cell Res, 2017b;27(8):1046–1064.
46.
LiC, DengY-Q, WangS, et al.25-Hydroxycholesterol protects host against Zika virus infection and its associated microcephaly in a mouse model. Immunity, 2017a;46(3):446–456.
47.
LiD, XieTT, GuoTY, et al.Sialic acid exerts anti-inflammatory effect through inhibiting MAPK-NF-kB/AP-1 pathway and apoptosis in ulcerative colitis. J Funct Foods, 2023; 101.
48.
LiC, XuD, YeQ, et al.Zika virus disrupts neural progenitor development and leads to microcephaly in mice. Cell Stem Cell, 2016; 19(1):120–126.
49.
LiM, ZhangD, LiC, et al.characterization of zika virus endocytic pathways in human glioblastoma cells. Front Microbiol, 2020; 11:242.
50.
LimontaD, JovelJ, KumarA, et al.Human fetal astrocytes infected with Zika virus exhibit delayed apoptosis and resistance to interferon: Implications for persistence. Viruses, 2018; 10(11):646.
51.
LindqvistR, MundtF, GilthorpeJD, et al.Fast type I interferon response protects astrocytes from flavivirus infection and virus-induced cytopathic effects. J Neuroinflammation, 2016; 13(1):277.
52.
LiuS, DeLalioLJ, IsaksonBE, WangTT. AXL-Mediated productive infection of human endothelial cells by Zika virus. Circ Res, 2016; 119(11):1183–1189.
53.
MeertensL, CarnecX, LecoinMP, et al.The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. Cell Host Microbe, 2012; 12(4):544–557.
54.
MeertensL, LabeauA, DejarnacO, et al.Axl mediates ZIKA virus entry in human glial cells and modulates innate immune responses. Cell Rep, 2017; 18(2):324–333.
55.
MinerJJ, CaoB, GoveroJ, et al.Zika virus infection during pregnancy in mice causes placental damage and fetal demise. Cell, 2016; 165(5):1081–1091.
56.
MlakarJ, KorvaM, TulN, et al.Zika virus associated with microcephaly. N Engl J Med, 2016; 374(10):951–958.
57.
ModisY, OgataS, ClementsD, HarrisonSC. Structure of the dengue virus envelope protein after membrane fusion. Nature, 2004; 427(6972):313–319.
58.
MouawadN, CapassoG, RuggeriE, et al.Is it still possible to think about HSP70 as a therapeutic target in onco-hematological diseases? Biomolecules, 2023; 13(4).
59.
MounceBC, CesaroT, CarrauL, et al.Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding. Antiviral Res, 2017; 142:148–157.
60.
MussoD, NhanT, RobinE, et al.Potential for Zika virus transmission through blood transfusion demonstrated during an outbreak in French Polynesia, November 2013 to February 2014. Eurosurveillance, 2014; 19(14):20761.
61.
Navarro-SanchezE, AltmeyerR, AmaraA, et al.Dendritic-cell-specific ICAM3-grabbing non-integrin is essential for the productive infection of human dendritic cells by mosquito-cell-derived dengue viruses. EMBO Rep, 2003; 4(7):723–728.
62.
NgosuwanJ, WangNM, FungKL, ChiricoWJ. Roles of cytosolic Hsp70 and Hsp40 molecular chaperones in post-translational translocation of presecretory proteins into the endoplasmic reticulum. J Biol Chem, 2003; 278(9):7034–7042.
63.
NowakowskiTJ, PollenAA, Di LulloE, et al.Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell, 2016; 18(5):591–596.
64.
OliveiraERA, de AlencastroRB, HortaBAC. New insights into flavivirus biology: The influence of pH over interactions between prM and E proteins. J Comput Aided Mol Des, 2017; 31(11):1009–1019.
65.
OwczarekK, ChykunovaY, JassoyC, et al.Zika virus: Mapping and reprogramming the entry. Cell Commun Signal, 2019; 17(1):41.
66.
PanayiotouC, LindqvistR, KurhadeC, et al.Viperin restricts Zika virus and tick-borne encephalitis virus replication by targeting NS3 for proteasomal degradation. J Virol, 2018; 92(12); doi: 10.1128/JVI.00501-18
67.
PapaMP, MeurenLM, CoelhoSV, et al.Zika virus infects, activates, and crosses brain microvascular endothelial cells, without barrier disruption. Front Microbiol, 2017; 8:2557.
68.
PersaudM, Martinez-LopezA, BuffoneC, et al.Infection by Zika viruses requires the transmembrane protein AXL, endocytosis and low pH. Virology, 2018; 518:301–312.
69.
PittsJD, LiPC, de WispelaereM, YangPL. Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus. Antiviral Res, 2017; 147:124–130.
70.
PujhariS, BrustolinM, MaciasV, et al.Heat shock protein 70 (Hsp70) mediates Zika virus entry, replication, and egress from host cells. Emerg Microbes Infect, 2019; 8(1):8–16.
71.
QuP, ZhangC, LiM, et al.A new class of broadly neutralizing antibodies that target the glycan loop of Zika virus envelope protein. Cell Discov, 2020; 6:5.
72.
RahimiN. C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell adhesion molecules turned to pathogen recognition receptors. Biology-Basel, 2021; 10.
73.
RauschK, HackettBA, WeinbrenNL, et al.Screening bioactives reveals nanchangmycin as a broad spectrum antiviral active against Zika virus. Cell Rep, 2017; 18(3):804–815.
74.
RetallackH, Di LulloE, AriasC, et al.Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proceedings of the National Academy of Sciences of the United States of America, 2016; 113(50):14408–14413.
75.
RivaL, GoellnerS, BieringSB, et al.The compound SBI-0090799 Inhibits Zika Virus Infection by Blocking De Novo Formation of the Membranous Replication Compartment. J Virol, 2021; 95(22):e0099621; doi: 10.1128/jvi.00996-21
76.
RobbianiDF, BozzaccoL, KeeffeJR, et al.Recurrent potent human neutralizing antibodies to zika virus in Brazil and Mexico. Cell, 2017; 169(4):597–609.e11.
77.
RouthuNK, LehouxSD, RouseEA, et al.Glycosylation of zika virus is important in host-virus interaction and pathogenic potential. Int J Mol Sci, 2019; 20(20):5206.
78.
RoyleJ, Ramírez-SantanaC, AkpunarlievaS, et al.Glucose-regulated Protein 78 interacts with zika virus envelope protein and contributes to a productive infection. Viruses, 2020; 12(5):524.
79.
SabinoC, BasicM, BenderD, et al.Bafilomycin A1 and U18666A efficiently impair ZIKV Infection. Viruses, 2019; 11(6):524.
80.
SacramentoCQ, de MeloGR, de FreitasCS, et al.The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Sci Rep, 2017; 7:40920.
81.
SapparapuG, FernandezE, KoseN, et al.Neutralizing human antibodies prevent Zika virus replication and fetal disease in mice. Nature, 2016; 540(7633):443–447.
82.
ShaoQ, HerrlingerS, YangS-L, et al.Zika virus infection disrupts neurovascular development and results in postnatal microcephaly with brain damage. Development (Cambridge, England), 2016; 143(22):4127–4136.
83.
ShiL, XiongH, HeJ, et al.Antiviral activity of arbidol against influenza A virus, respiratory syncytial virus, rhinovirus, coxsackie virus and adenovirus in vitro and in vivo. Arch Virol, 2007; 152(8):1447–1455.
84.
ShiryaevSA, MesciP, PintoA, et al.Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis. Sci Rep, 2017; 7(1):15771.
85.
SirohiD, ChenZ, SunL, et al.The 3.8 Å resolution cryo-EM structure of Zika virus. Science, 2016; 352(6284):467–470.
86.
SrivastavaM, ZhangY, ChenJ, et al.Chemical proteomics tracks virus entry and uncovers NCAM1 as Zika virus receptor. Nat Commun, 2020; 11(1):3896.
87.
StrangeDP, JiyaromB, Pourhabibi ZarandiN, et al.Axl promotes zika virus entry and modulates the antiviral state of human Sertoli cells. MBio, 2019; 10(4):10–128.
88.
SunFC, WeiS, LiCW, et al.Localization of GRP78 to mitochondria under the unfolded protein response. Biochem J, 2006; 396(1):31–39.
89.
TabataT, PetittM, Puerta-GuardoH, et al.Zika virus targets different primary human placental cells, suggesting two routes for vertical transmission. Cell Host Microbe, 2016; 20(2):155–166.
TangH, HammackC, OgdenSC, et al.Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell, 2016; 18(5):587–590.
93.
TassaneetrithepB, BurgessTH, Granelli-PipernoA, et al.DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J Exp Med, 2003; 197(7):823–829.
94.
TongX, SmithJ, BukreyevaN, et al.Merimepodib, an IMPDH inhibitor, suppresses replication of Zika virus and other emerging viral pathogens. Antiviral Res, 2018; 149:34–40.
van den PolAN, MaoG, YangY, et al.Zika virus targeting in the developing brain. J Neurosci, 2017; 37(8):2161–2175.
97.
van der SchaarHM, RustMJ, ChenC, et al.Dissecting the cell entry pathway of dengue virus by single-particle tracking in living cells. PLoS Pathog, 2008; 4(12):e1000244.
98.
VegaVL, Rodriguez-SilvaM, FreyT, et al.Hsp70 translocates into the plasma membrane after stress and is released into the extracellular environment in a membrane-associated form that activates macrophages. J Immunol, 2008; 180(6):4299–4307.
99.
VeneroC, HerreroAI, TouyarotK, et al.Hippocampal up-regulation of NCAM expression and polysialylation plays a key role on spatial memory. Eur J Neurosci, 2006; 23(6):1585–1595.
100.
VigS, BuitingaM, RondasD, et al.Cytokine-induced translocation of GRP78 to the plasma membrane triggers a pro-apoptotic feedback loop in pancreatic beta cells. Cell Death Dis, 2019; 10(4):309.
101.
VukojevicV, MastrandreasP, ArnoldA, et al.Evolutionary conserved role of neural cell adhesion molecule-1 in memory. Transl Psychiatry, 2020; 10(1):217.
102.
WangJ, LiuJ, ZhouR, et al.Zika virus infected primary microglia impairs NPCs proliferation and differentiation. Biochem Biophys Res Commun, 2018; 497(2):619–625.
103.
WangLH, RothbergKG, AndersonRG. Mis-assembly of clathrin lattices on endosomes reveals a regulatory switch for coated pit formation. J Cell Biol, 1993; 123(5):1107–1117.
104.
WangQ, YangH, LiuX, et al.Molecular determinants of human neutralizing antibodies isolated from a patient infected with Zika virus. Sci Transl Med, 2016; 8(369):369ra179.
105.
WellsMF, SalickMR, WiskowO, et al.Genetic ablation of AXL does not protect human neural progenitor cells and cerebral organoids from zika virus infection. Cell Stem Cell, 2016; 19(6):703–708.
106.
WobstH, SchmitzB, SchachnerM, et al.Kinesin-1 promotes post-Golgi trafficking of NCAM140 and NCAM180 to the cell surface. J Cell Sci, 2015; 128(15):2816–2829.
107.
XuM, LeeEM, WenZ, et al.Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med, 2016; 22(10):1101–1107.
108.
XueZW, ZhaoH, ZhuR, et al.On the use of abiotic sialic acids to attenuate cell inflammation. Sci Rep, 2018; 8(1):17320.
109.
YangHQ, LuLP, ChenXZ. An overview and future prospects of sialic acids. Biotechnol Adv, 2021; 46.
110.
YuL, LiuX, YeX, et al.Monoclonal Antibodies against Zika Virus NS1 Protein Confer Protection via Fcγ Receptor-Dependent and -Independent Pathways. MBio, 2021; 12(1):10–128.
111.
YunSI, SongBH, FrankJC, et al.Complete genome sequences of three historically important, spatiotemporally distinct, and genetically divergent strains of Zika virus: MR-766, P6-740, and PRVABC-59. Genome Announc, 2016; 4(4).
112.
ZanlucaC, MeloVC, MosimannAL, et al.First report of autochthonous transmission of Zika virus in Brazil. Mem Inst Oswaldo Cruz, 2015; 110(4):569–572.
113.
ZhangS, KostyuchenkoVA, NgT-S, et al.Neutralization mechanism of a highly potent antibody against Zika virus. Nat Commun, 2016; 7:13679.
114.
ZhangD, ZhaoY, WangL, et al.Axl mediates resistance to respiratory syncytial virus infection independent of cell attachment. Am J Respir Cell Mol Biol, 2022; 67(2):227–240.
115.
ZmurkoJ, MarquesRE, ScholsD, et al.The viral polymerase inhibitor 7-deaza-2′-C-methyladenosine is a potent inhibitor of in vitro Zika virus replication and delays disease progression in a robust mouse infection model. PLoS Negl Trop Dis, 2016; 10(5):e0004695.
