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Research progress on pathogenic and therapeutic mechanisms of Enterovirus A71

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Abstract

In recent years, enterovirus A71 (EV-A71) infection has become a major global public health problem, especially for infants and young children. The results of epidemiological research show that EV-A71 infection can cause acute hand, foot, and mouth disease (HFMD) and complications of the nervous system in severe cases, including aseptic pediatric meningoencephalitis, acute flaccid paralysis, and even death. Many studies have demonstrated that EV-A71 infection may trigger a variety of intercellular and intracellular signaling pathways, which are interconnected to form a network that leads to the innate immune response, immune escape, inflammation, and apoptosis in the host. This article aims to provide an overview of the possible mechanisms underlying infection, signaling pathway activation, the immune response, immune evasion, apoptosis, and the inflammatory response caused by EV-A71 infection and an overview of potential therapeutic strategies against EV-A71 infection to better understand the pathogenesis of EV-A71 and to aid in the development of antiviral drugs and vaccines.

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Abbreviations

HFMD:

hand, foot, and mouth disease

EV-A71:

enterovirus A71

RNA:

ribonucleic acid

CV:

coxsackievirus

PAMPs:

pathogen-associated molecular patterns

SCARB2:

scavenger receptor B2

PRRs:

pattern recognition receptors

RD:

rhabdomyosarcoma

UTR:

untranslated region

eIF4E:

eukaryotic initiation factor 4E

eIF3:

eukaryotic initiation factor 3

RdRp:

RNA-dependent RNA polymerase

PABP:

poly(A)-binding protein

DNA:

deoxyribonucleic acid

VP:

viral protein

P1:

precursor protein 1

hSCARB2:

human scavenger receptor class B, member 2

HS:

heparan sulfate

PSGL-1:

P-selectin glycoprotein ligand 1

Anx2:

annexin II

PHBs:

prohibitins

HSP90β:

heat shock protein 90β

GA:

geldanamycin

17-AAG:

analogue 17-allyamino-17-demethoxygeldanamycin

HSP90:

heat shock protein 90

CNS:

central nervous system

PRPH:

peripherin

BBB:

blood-brain barrier

IFNAR:

interferon-α receptor

RAT:

retrograde axonal transport

NMJs:

neuromuscular junctions

UGGT1:

UDP-glucose glycoprotein glucosyltransferase 1

CpG:

cytidine phosphoguanosine

MDA5:

melanoma differentiation associated gene 5

IFN:

interferon

ISG:

IFN-stimulated gene

CaMKII:

calmodulin-dependent protein kinase II

AIF:

apoptosis-inducing factor

MAPK:

mitogen-activated protein kinase

BMK1:

big MAP kinase 1

EGFR:

epidermal growth factor receptor

COX-2:

cyclooxygenase-2

PGE2:

prostaglandin E2

OS:

oxidative stress

ROS:

reactive oxygen species

NF-κB:

nuclear factor kappa B

OAS3:

oligoadenylate synthetase 3

IRF9:

IFN regulatory factor 9

ISREs:

IFN-stimulated response elements

iIELs:

intraepithelial lymphocytes

iNK:

intestinal NK cells

PP1:

protein phosphatase 1

IKKβ:

inhibitor of kappa B kinase β

FDA:

Food and Drug Administration

IMPDH:

hypoxanthine dehydrogenase

GTP:

guanosine triphosphate

AIM:

absent in melanoma

ASC:

apoptosis-associated speck-like protein containing CARD domain

SAT1:

spermidine-spermine N1 acetyltransferase

NLRP3:

NOD-like receptor thermal protein domain associated protein 3

NLR:

NOD-like receptor

2CL:

2C ligand

SELEX:

systematic evolution of ligands by exponential enrichment

CPE:

cytopathic effect

pIY:

miRNA-based attenuated live vaccine strain

SAVE:

synthetic attenuated virus engineering

VLPs:

virus-like particles

IRES:

internal ribosome entry site

BRAF:

V-Raf murine sarcoma viral oncogene homolog B1

CTL:

cytotoxic T lymphocyte

UpA:

uridine adenosine phosphate

References

  1. Cox B, Levent F (2018) Hand, Foot, and Mouth Disease. JAMA 320:2492. https://doi.org/10.1001/jama.2018.17288

    Article  PubMed  Google Scholar 

  2. Gonzalez G, Carr MJ, Kobayashi M et al (2019) Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World. IJMS 20:5201. https://doi.org/10.3390/ijms20205201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bruu A-L (2002) Enteroviruses: Polioviruses, Coxsackieviruses, Echoviruses and Newer Enteroviruses. In: Haaheim LR, Pattison JR, Whitley RJ (eds) A Practical Guide to Clinical Virology. John Wiley & Sons, Ltd, Chichester, UK, pp 44–45

    Chapter  Google Scholar 

  4. Chavan NA, Lavania M, Shinde P et al (2023) The 2022 outbreak and the pathobiology of the coxsackie virus [hand foot and mouth disease] in India. Infect Genet Evol 111:105432. https://doi.org/10.1016/j.meegid.2023.105432

    Article  PubMed  Google Scholar 

  5. Messacar K, Abzug MJ, Dominguez SR (2016) The Emergence of Enterovirus-D68. https://doi.org/10.1128/microbiolspec.EI10-0018-2016. Microbiol Spectr 4:

  6. Schmidt NJ, Lennette EH, Ho HH (1974) An Apparently New Enterovirus Isolated from Patients with Disease of the Central Nervous System. J Infect Dis 129:304–309. https://doi.org/10.1093/infdis/129.3.304

    Article  CAS  PubMed  Google Scholar 

  7. Chen K-T, Chang H-L, Wang S-T et al (2007) Epidemiologic Features of Hand-Foot-Mouth Disease and Herpangina Caused by Enterovirus 71 in Taiwan, 1998–2005. Pediatrics 120:e244–e252. https://doi.org/10.1542/peds.2006-3331

    Article  PubMed  Google Scholar 

  8. Cardosa MJ, Krishnan S, Tio PH et al (1999) Isolation of subgenus B adenovirus during a fatal outbreak of enterovirus 71-associated hand, foot, and mouth disease in Sibu, Sarawak. The Lancet 354:987–991. https://doi.org/10.1016/S0140-6736(98)11032-2

    Article  CAS  Google Scholar 

  9. Chan KP, Goh KT, Chong CY et al (2003) Epidemic Hand, Foot and Mouth Disease Caused by Human Enterovirus 71, Singapore. Emerg Infect Dis 9

  10. Chan LG, Parashar UD, Lye MS et al (2000) Deaths of Children during an Outbreak of Hand, Foot, and Mouth Disease in Sarawak, Malaysia: Clinical and Pathological Characteristics of the Disease. Clin Infect Dis 31:678–683. https://doi.org/10.1086/314032

    Article  CAS  PubMed  Google Scholar 

  11. Ho M, Chen E-R, Hsu K-H et al (1999) An Epidemic of Enterovirus 71 Infection in Taiwan. N Engl J Med 341:929–935. https://doi.org/10.1056/NEJM199909233411301

    Article  CAS  PubMed  Google Scholar 

  12. McMinn P, Stratov I, Nagarajan L, Davis S (2001) Neurological Manifestations of Enterovirus 71 Infection in Children during an Outbreak of Hand, Foot, and Mouth Disease in Western Australia. Clin Infect Dis 32:236–242. https://doi.org/10.1086/318454

    Article  CAS  PubMed  Google Scholar 

  13. Van Tu P, Thao NTT, Perera D et al (2007) Epidemiologic and Virologic Investigation of Hand, Foot, and Mouth Disease, Southern Vietnam, 2005. Emerg Infect Dis 13:1733–1741. https://doi.org/10.3201/eid1311.070632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang Y, Tan X-J, Wang H-Y et al (2009) An outbreak of hand, foot, and mouth disease associated with subgenotype C4 of human enterovirus 71 in Shandong, China. J Clin Virol 44:262–267. https://doi.org/10.1016/j.jcv.2009.02.002

    Article  PubMed  Google Scholar 

  15. Komatsu H, Shimizu Y, Takeuchi Y et al (1999) Outbreak of severe neurologic involvement associated with enterovirus 71 infection. Pediatr Neurol 20:17–23. https://doi.org/10.1016/S0887-8994(98)00087-3

    Article  CAS  PubMed  Google Scholar 

  16. Zhang Y, Zhu Z, Yang W et al (2010) An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of Hand Foot and Mouth Disease in Fuyang city of China. Virol J 7:1–9. https://doi.org/10.1186/1743-422X-7-94

    Article  CAS  Google Scholar 

  17. M H (2000) Enterovirus 71: the virus, its infections and outbreaks. J Microbiol Immunol Infect 33:205–216

  18. Gobara F, Itagaki A, Ito Y et al (1977) Properties of Virus Isolated from an Epidemic of Hand-Foot-and-Mouth Disease in 1973 in the City of Matsue: Comparison with Coxsackievirus Group A Type 16 Prototype. Microbiol Immunol 21:207–217. https://doi.org/10.1111/j.1348-0421.1977.tb00282.x

    Article  CAS  PubMed  Google Scholar 

  19. Hagiwara A, Tagaya I, Yoneyama T (1978) Epidemic of Hand, Foot and Mouth Disease Associated with Enterovirus 71 Infection. Intervirology 9:60–63. https://doi.org/10.1159/000148922

    Article  CAS  PubMed  Google Scholar 

  20. Gilbert GL, Dickson KE, Waters M-J et al (1988) Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement: The Pediatric. Infect Disease J 7:484–487. https://doi.org/10.1097/00006454-198807000-00007

    Article  CAS  Google Scholar 

  21. An L, Ga K, Va L, Mi M (2009) [Enterovirus 71: epidemiology and diagnostics]. Zhurnal mikrobiologii, epidemiologii i immunobiologii

  22. Zhang Y, Tan X, Cui A et al (2013) Complete Genome Analysis of the C4 Subgenotype Strains of Enterovirus 71: Predominant Recombination C4 Viruses Persistently Circulating in China for 14 Years. PLoS ONE 8:e56341. https://doi.org/10.1371/journal.pone.0056341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mizuta K, Aoki Y, Matoba Y et al (2014) Molecular epidemiology of enterovirus 71 strains isolated from children in Yamagata, Japan, between 1990 and 2013. J Med Microbiol 63:1356–1362. https://doi.org/10.1099/jmm.0.079699-0

    Article  PubMed  Google Scholar 

  24. Zhou J, Shi Y, Miao L et al (2021) Molecular epidemiology and recombination of Enterovirus A71 in mainland China from 1987 to 2017. Int Microbiol 24:291–299. https://doi.org/10.1007/s10123-021-00164-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Huang Y-P, Lin T-L, Lin T-H, Wu H-S (2013) Antigenic and Genetic Diversity of Human Enterovirus 71 from 2009 to 2012, Taiwan. PLoS ONE 8:e80942. https://doi.org/10.1371/journal.pone.0080942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. World Health Organization. Regional Office for the Western Pacific (2018) Hand, Foot and Mouth Disease Situation Update 2018. WHO Regional Office for the Western Pacific, Manila

    Google Scholar 

  27. Pallansch MA, Oberste MS, Whitton J (2013) Enteroviruses: Polioviruses, coxsackieviruses, echoviruses, and newer enteroviruses. Fields Virol 490–530. https://doi.org/10.1002/0470857285.ch6

  28. Takeuchi O, Akira S (2010) Pattern Recognition Receptors and Inflammation. Cell 140:805–820. https://doi.org/10.1016/j.cell.2010.01.022

    Article  CAS  PubMed  Google Scholar 

  29. Sun M, Yan K, Wang C et al (2021) Intrinsic apoptosis and cytokine induction regulated in human tonsillar epithelial cells infected with enterovirus A71. PLoS ONE 16:e0245529. https://doi.org/10.1371/journal.pone.0245529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Swain SK, Panda S, Sahu BP, Sarangi R (2022) Activation of Host Cellular Signaling and Mechanism of Enterovirus 71 Viral Proteins Associated with Hand, Foot and Mouth Disease. Viruses 14:2190. https://doi.org/10.3390/v14102190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lu J-R, Lu W-W, Lai J-Z et al (2013) Calcium flux and calpain-mediated activation of the apoptosis-inducing factor contribute to enterovirus 71-induced apoptosis. J Gen Virol 94:1477–1485. https://doi.org/10.1099/vir.0.047753-0

    Article  CAS  PubMed  Google Scholar 

  32. Haolong C, Du N, Hongchao T et al (2013) Enterovirus 71 VP1 activates calmodulin-dependent protein kinase II and results in the rearrangement of vimentin in human astrocyte cells. PLoS ONE 8:e73900. https://doi.org/10.1371/journal.pone.0073900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen K-R, Ling P (2019) Interplays between Enterovirus A71 and the innate immune system. J Biomed Sci 26:95. https://doi.org/10.1186/s12929-019-0596-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wu W, Wages PA, Devlin RB et al (2015) Src-Mediated EGF Receptor Activation Regulates Ozone-Induced Interleukin 8 Expression in Human Bronchial Epithelial Cells. Environ Health Perspect 123:231–236. https://doi.org/10.1289/ehp.1307379

    Article  PubMed  Google Scholar 

  35. Lei X, Han N, **ao X et al (2014) Enterovirus 71 3C Inhibits Cytokine Expression through Cleavage of the TAK1/TAB1/TAB2/TAB3 Complex. J Virol 88:9830–9841. https://doi.org/10.1128/JVI.01425-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Leong SY, Ong BKT, Chu JJH (2015) The Role of Misshapen NCK-related kinase (MINK), a Novel Ste20 Family Kinase, in the IRES-Mediated Protein Translation of Human Enterovirus 71. PLoS Pathog 11:e1004686. https://doi.org/10.1371/journal.ppat.1004686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. **e G-C, Guo N-J, Grénman R et al (2016) Susceptibility of human tonsillar epithelial cells to enterovirus 71 with normal cytokine response. Virology 494:108–118. https://doi.org/10.1016/j.virol.2016.04.016

    Article  CAS  PubMed  Google Scholar 

  38. Madrid LV, Wang C-Y, Guttridge DC et al (2000) Akt Suppresses Apoptosis by Stimulating the Transactivation Potential of the RelA/p65 Subunit of NF-κB. Mol Cell Biol 20:1626–1638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lv X, Qiu M, Chen D et al (2014) Apigenin inhibits enterovirus 71 replication through suppressing viral IRES activity and modulating cellular JNK pathway. Antiviral Res 109:30–41. https://doi.org/10.1016/j.antiviral.2014.06.004

    Article  CAS  PubMed  Google Scholar 

  40. Song J, Hu Y, Li J et al (2018) Suppression of the toll-like receptor 7-dependent type I interferon production pathway by autophagy resulting from enterovirus 71 and coxsackievirus A16 infections facilitates their replication. Arch Virol 163:135–144. https://doi.org/10.1007/s00705-017-3592-x

    Article  CAS  PubMed  Google Scholar 

  41. Du H, Yin P, Yang X et al (2015) Enterovirus 71 2C Protein Inhibits NF-κB Activation by Binding to RelA(p65). Sci Rep 5:14302. https://doi.org/10.1038/srep14302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tung W-H, Lee I-T, Hsieh H-L, Yang C-M (2010) EV71 induces COX-2 expression via c-Src/PDGFR/PI3K/Akt/p42/p44 MAPK/AP-1 and NF-κB in rat brain astrocytes. J Cell Physiol 224:376–386. https://doi.org/10.1002/jcp.22133

    Article  CAS  PubMed  Google Scholar 

  43. Dang D, Zhang C, Zhang R et al (2017) Involvement of inducible nitric oxide synthase and mitochondrial dysfunction in the pathogenesis of enterovirus 71 infection. Oncotarget 8:81014–81026. https://doi.org/10.18632/oncotarget.21250

    Article  PubMed  PubMed Central  Google Scholar 

  44. Zheng B, Zhou X, Tian L et al (2022) IFN-β1b induces OAS3 to inhibit EV71 via IFN-β1b/JAK/STAT1 pathway. Virol Sin 37:676–684. https://doi.org/10.1016/j.virs.2022.07.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liu M-L, Lee Y-P, Wang Y-F et al (2005) Type I interferons protect mice against enterovirus 71 infection. J Gen Virol 86:3263–3269. https://doi.org/10.1099/vir.0.81195-0

    Article  CAS  PubMed  Google Scholar 

  46. Huang CC, Liu CC, Chang YC et al (1999) Neurologic complications in children with enterovirus 71 infection. N Engl J Med 341:936–942. https://doi.org/10.1056/NEJM199909233411302

    Article  CAS  PubMed  Google Scholar 

  47. Sun J, Ennis J, Turner JD, Chu JJH (2016) Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge. Antiviral Res 134:207–215. https://doi.org/10.1016/j.antiviral.2016.09.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sadeghipour S, Bek EJ, McMinn PC (2013) Ribavirin-resistant mutants of human enterovirus 71 express a high replication fidelity phenotype during growth in cell culture. J Virol 87:1759–1769. https://doi.org/10.1128/JVI.02139-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Fang S-H, Hwang L-H, Chen D-S, Chiang B-L (2000) Ribavirin enhancement of hepatitis C virus core antigen-specific type 1 T helper cell response correlates with the increased IL-12 level. J Hepatol 33:791–798. https://doi.org/10.1016/S0168-8278(00)80312-8

    Article  CAS  PubMed  Google Scholar 

  50. Zuckerman E (2001) The effect of antiviral therapy on t(14;18) translocation and immunoglobulin gene rearrangement in patients with chronic hepatitis C virus infection. Blood 97:1555–1559. https://doi.org/10.1182/blood.V97.6.1555

    Article  CAS  PubMed  Google Scholar 

  51. Dai W, Bi J, Li F et al (2019) Antiviral Efficacy of Flavonoids against Enterovirus 71 Infection in Vitro and in Newborn Mice. https://doi.org/10.3390/v11070625. Viruses 11:

  52. Hu B, Chik KK-H, Chan JF-W et al (2022) Vemurafenib Inhibits Enterovirus A71 Genome Replication and Virus Assembly. Pharmaceuticals (Basel) 15. https://doi.org/10.3390/ph15091067

  53. Zou X, Wu J, Gu J et al (2021) DNA aptamer against EV-A71 VP1 protein: selection and application. Virol J 18:164. https://doi.org/10.1186/s12985-021-01631-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Liu X, Yang W, Zhang C et al (2021) Immunogenicity and safety of an inactivated enterovirus 71 vaccine co-administered with measles-mumps-rubella vaccine and live-attenuated Japanese encephalitis vaccine: a phase 4, single-center, randomized controlled trial. Hum Vaccin Immunother 17:5348–5354. https://doi.org/10.1080/21645515.2021.2010428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhu F, Xu W, **a J et al (2014) Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N Engl J Med 370:818–828. https://doi.org/10.1056/NEJMoa1304923

    Article  CAS  PubMed  Google Scholar 

  56. Guan X, Che Y, Wei S et al (2020) Effectiveness and Safety of an Inactivated Enterovirus 71 Vaccine in Children Aged 6–71 Months in a Phase IV Study. Clin Infect Dis 71:2421–2427. https://doi.org/10.1093/cid/ciz1114

    Article  CAS  PubMed  Google Scholar 

  57. Hwa S-H, Lee YA, Brewoo JN et al (2013) Preclinical evaluation of the immunogenicity and safety of an inactivated enterovirus 71 candidate vaccine. PLoS Negl Trop Dis 7:e2538. https://doi.org/10.1371/journal.pntd.0002538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Chang J-Y, Chang C-P, Tsai HH-P et al (2012) Selection and characterization of vaccine strain for Enterovirus 71 vaccine development. Vaccine 30:703–711. https://doi.org/10.1016/j.vaccine.2011.11.087

    Article  CAS  PubMed  Google Scholar 

  59. Yee PTI, Tan SH, Ong KC et al (2019) Development of live attenuated Enterovirus 71 vaccine strains that confer protection against lethal challenge in mice. Sci Rep 9:4805. https://doi.org/10.1038/s41598-019-41285-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Tsai Y-H, Huang S-W, Hsieh W-S et al (2019) Enterovirus A71 Containing Codon-Deoptimized VP1 and High-Fidelity Polymerase as Next-Generation Vaccine Candidate. J Virol 93. https://doi.org/10.1128/JVI.02308-18

  61. Yang Z, Gao F, Wang X et al (2020) Development and characterization of an enterovirus 71 (EV71) virus-like particles (VLPs) vaccine produced in Pichia pastoris. Hum Vaccin Immunother 16:1602–1610. https://doi.org/10.1080/21645515.2019.1649554

    Article  CAS  PubMed  Google Scholar 

  62. Kim H-J, Son HS, Lee SW et al (2019) Efficient expression of enterovirus 71 based on virus-like particles vaccine. PLoS ONE 14:e0210477. https://doi.org/10.1371/journal.pone.0210477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lei L, Li Q, Xu S et al (2021) Transplantation of Enterovirus 71 Virion Protein Particle Vaccine Protects Against Enterovirus 71 Infection in a Neonatal Mouse Model. Ann Transpl 26:e924461. https://doi.org/10.12659/AOT.924461

    Article  CAS  Google Scholar 

  64. Cox JA, Hiscox JA, Solomon T et al (2017) Immunopathogenesis and Virus–Host Interactions of Enterovirus 71 in Patients with Hand, Foot and Mouth Disease. Front Microbiol 8:2249. https://doi.org/10.3389/fmicb.2017.02249

    Article  PubMed  PubMed Central  Google Scholar 

  65. Yamayoshi S, Yamashita Y, Li J et al (2009) Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med 15:798–801. https://doi.org/10.1038/nm.1992

    Article  CAS  PubMed  Google Scholar 

  66. Yamayoshi S, Ohka S, Fujii K, Koike S (2013) Functional Comparison of SCARB2 and PSGL1 as Receptors for Enterovirus 71. J Virol 87:3335–3347. https://doi.org/10.1128/JVI.02070-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tan CW, Poh CL, Sam I-C, Chan YF (2013) Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor. J Virol 87:611–620. https://doi.org/10.1128/JVI.02226-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nishimura Y, Shimojima M, Tano Y et al (2009) Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med 15:794–797. https://doi.org/10.1038/nm.1961

    Article  CAS  PubMed  Google Scholar 

  69. Su P-Y, Liu Y-T, Chang H-Y et al (2012) Cell surface sialylation affects binding of enterovirus 71 to rhabdomyosarcoma and neuroblastoma cells. BMC Microbiol 12:162. https://doi.org/10.1186/1471-2180-12-162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yang B, Chuang H, Yang KD (2009) Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to DLD-1 intestinal cells. Virol J 6:141. https://doi.org/10.1186/1743-422X-6-141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yang B, Solakyildirim K, Chang Y, Linhardt RJ (2011) Hyphenated techniques for the analysis of heparin and heparan sulfate. Anal Bioanal Chem 399:541–557. https://doi.org/10.1007/s00216-010-4117-6

    Article  CAS  PubMed  Google Scholar 

  72. Du N, Cong H, Tian H et al (2014) Cell Surface Vimentin Is an Attachment Receptor for Enterovirus 71. J Virol 88:5816–5833. https://doi.org/10.1128/JVI.03826-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Su P-Y, Wang Y-F, Huang S-W et al (2015) Cell Surface Nucleolin Facilitates Enterovirus 71 Binding and Infection. J Virol 89:4527–4538. https://doi.org/10.1128/JVI.03498-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. He Q, Ren S, **a Z et al (2018) Fibronectin Facilitates Enterovirus 71 Infection by Mediating Viral Entry. J Virol 92:e02251–e02217. https://doi.org/10.1128/JVI.02251-17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lin H-Y, Yang Y-T, Yu S-L et al (2013) Caveolar Endocytosis Is Required for Human PSGL-1-Mediated Enterovirus 71 Infection. J Virol 87:9064–9076. https://doi.org/10.1128/JVI.00573-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Wang S, Pang Z, Fan H, Tong Y (2023) Advances in anti-EV-A71 drug development research. J Adv Res S2090-1232(23)00089–9. https://doi.org/10.1016/j.jare.2023.03.007

  77. Bavelloni A, Piazzi M, Raffini M et al (2015) Prohibitin 2: At a communications crossroads. IUBMB Life 67:239–254. https://doi.org/10.1002/iub.1366

    Article  CAS  PubMed  Google Scholar 

  78. Lim ZQ, Ng QY, Oo Y et al (2021) Enterovirus-A71 exploits peripherin and Rac1 to invade the central nervous system. EMBO Rep 22. https://doi.org/10.15252/embr.202051777

  79. Tsou Y-L, Lin Y-W, Chang H-W et al (2013) Heat Shock protein 90: Role in Enterovirus 71 Entry and Assembly and Potential Target for Therapy. PLoS ONE 8:e77133. https://doi.org/10.1371/journal.pone.0077133

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Lee K-M, Wu C-C, Wu S-E et al (2020) The RNA-dependent RNA polymerase of enterovirus A71 associates with ribosomal proteins and positively regulates protein translation. RNA Biol 17:608–622. https://doi.org/10.1080/15476286.2020.1722448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Solomon T, Lewthwaite P, Perera D et al (2010) Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 10:778–790. https://doi.org/10.1016/S1473-3099(10)70194-8

    Article  PubMed  Google Scholar 

  82. Song Y, Cheng X, Yang X et al (2015) Early growth response-1 facilitates enterovirus 71 replication by direct binding to the viral genome RNA. Int J Biochem Cell Biol 62:36–46. https://doi.org/10.1016/j.biocel.2015.02.012

    Article  CAS  PubMed  Google Scholar 

  83. Wang H, Li Y (2019) Recent Progress on Functional Genomics Research of Enterovirus 71. Virol Sin 34:9–21. https://doi.org/10.1007/s12250-018-0071-9

    Article  CAS  PubMed  Google Scholar 

  84. Huang H-I, Lin J-Y, Chiang H-C et al (2020) Exosomes Facilitate Transmission of Enterovirus A71 From Human Intestinal Epithelial Cells. J Infect Dis 222:456–469. https://doi.org/10.1093/infdis/jiaa174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Jiao X-Y, Guo L, Huang D-Y et al (2014) Distribution of EV71 receptors SCARB2 and PSGL-1 in human tissues. Virus Res 190:40–52. https://doi.org/10.1016/j.virusres.2014.05.007

    Article  CAS  PubMed  Google Scholar 

  86. Sun L, Tijsma A, Mirabelli C et al (2019) Intra-host emergence of an enterovirus A71 variant with enhanced PSGL1 usage and neurovirulence. Emerg Microbes Infections 8:1076–1085. https://doi.org/10.1080/22221751.2019.1644142

    Article  CAS  Google Scholar 

  87. Liu K, Ma Y, Zhang C et al (2012) [Neurologic complications in children with enterovirus 71-infected hand-foot-mouth disease: clinical features, MRI findings and follow-up study]. Zhonghua Yi Xue Za Zhi 92:1742–1746

    PubMed  Google Scholar 

  88. Zhao T, Zhang Z, Zhang Y et al (2017) Dynamic Interaction of Enterovirus 71 and Dendritic Cells in Infected Neonatal Rhesus Macaques. Front Cell Infect Microbiol 7:171. https://doi.org/10.3389/fcimb.2017.00171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chen C-S, Yao Y-C, Lin S-C et al (2007) Retrograde Axonal Transport: a Major Transmission Route of Enterovirus 71 in Mice. J Virol 81:8996–9003. https://doi.org/10.1128/JVI.00236-07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chang C-S, Liao C-C, Liou A-T et al (2019) Enterovirus 71 targets the cardiopulmonary system in a robust oral infection mouse model. Sci Rep 9:11108. https://doi.org/10.1038/s41598-019-47455-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang W, Sun J, Wang N et al (2020) Enterovirus A71 capsid protein VP1 increases blood–brain barrier permeability and virus receptor vimentin on the brain endothelial cells. J Neurovirol 26:84–94. https://doi.org/10.1007/s13365-019-00800-8

    Article  CAS  PubMed  Google Scholar 

  92. Chen Y-C, Yu C-K, Wang Y-F et al (2004) A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol 85:69–77. https://doi.org/10.1099/vir.0.19423-0

    Article  CAS  PubMed  Google Scholar 

  93. Khong WX, Yan B, Yeo H et al (2012) A Non-Mouse-Adapted Enterovirus 71 (EV71) Strain Exhibits Neurotropism, Causing Neurological Manifestations in a Novel Mouse Model of EV71 Infection. J Virol 86:2121–2131. https://doi.org/10.1128/JVI.06103-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Huang P-N, Jheng J-R, Arnold JJ et al (2017) UGGT1 enhances enterovirus 71 pathogenicity by promoting viral RNA synthesis and viral replication. PLoS Pathog 13:e1006375. https://doi.org/10.1371/journal.ppat.1006375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Pathinayake PS, Hsu AC-Y, Wark PAB (2015) Innate Immunity and Immune Evasion by Enterovirus 71. Viruses 7:6613–6630. https://doi.org/10.3390/v7122961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lei X, **ao X, Wang J (2016) Innate Immunity Evasion by Enteroviruses: Insights into Virus-Host Interaction. Viruses 8:22. https://doi.org/10.3390/v8010022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Xagorari A, Chlichlia K (2008) Toll-Like Receptors and Viruses: Induction of Innate Antiviral Immune Responses. TOMICROJ 2:49–59. https://doi.org/10.2174/1874285800802010049

    Article  CAS  Google Scholar 

  98. Kato H, Takeuchi O, Sato S et al (2006) Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441:101–105. https://doi.org/10.1038/nature04734

    Article  CAS  PubMed  Google Scholar 

  99. Hornung V, Ellegast J, Kim S et al (2006) 5’-Triphosphate RNA Is the Ligand for RIG-I. Science 314:994–997. https://doi.org/10.1126/science.1132505

    Article  PubMed  Google Scholar 

  100. García-Sastre A (2017) Ten Strategies of Interferon Evasion by Viruses. Cell Host Microbe 22:176–184. https://doi.org/10.1016/j.chom.2017.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bowie AG, Unterholzner L (2008) Viral evasion and subversion of pattern-recognition receptor signalling. Nat Rev Immunol 8:911–922. https://doi.org/10.1038/nri2436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kontsek P (1994) Human type I interferons: structure and function. Acta Virol 38:345–360

    CAS  PubMed  Google Scholar 

  103. Reid E, Charleston B (2014) Type I and III Interferon Production in Response to RNA Viruses. J Interferon Cytokine Res 34:649–658. https://doi.org/10.1089/jir.2014.0066

    Article  CAS  PubMed  Google Scholar 

  104. Kawai T, Akira S (2011) Toll-like Receptors and Their Crosstalk with Other Innate Receptors in Infection and Immunity. Immunity 34:637–650. https://doi.org/10.1016/j.immuni.2011.05.006

    Article  CAS  PubMed  Google Scholar 

  105. Chow J, Franz KM, Kagan JC (2015) PRRs are watching you: Localization of innate sensing and signaling regulators. Virology 479–480:104–109. https://doi.org/10.1016/j.virol.2015.02.051

    Article  CAS  PubMed  Google Scholar 

  106. McNab F, Mayer-Barber K, Sher A et al (2015) Type I interferons in infectious disease. Nat Rev Immunol 15:87–103. https://doi.org/10.1038/nri3787

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kuo R-L, Chen Y-T, Li H-A et al (2021) Molecular determinants and heterogeneity underlying host response to EV-A71 infection at single-cell resolution. RNA Biol 18:796–808. https://doi.org/10.1080/15476286.2021.1872976

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Dong Y, Liu J, Lu N, Zhang C (2021) Enterovirus 71 Antagonizes Antiviral Effects of Type III Interferon and Evades the Clearance of Intestinal Intraepithelial Lymphocytes. Front Microbiol 12:806084. https://doi.org/10.3389/fmicb.2021.806084

    Article  PubMed  Google Scholar 

  109. Weng K-F, Li M-L, Hung C-T, Shih S-R (2009) Enterovirus 71 3C protease cleaves a novel target CstF-64 and inhibits cellular polyadenylation. PLoS Pathog 5:e1000593. https://doi.org/10.1371/journal.ppat.1000593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wang T, Wang B, Huang H et al (2017) Enterovirus 71 protease 2Apro and 3Cpro differentially inhibit the cellular endoplasmic reticulum-associated degradation (ERAD) pathway via distinct mechanisms, and enterovirus 71 hijacks ERAD component p97 to promote its replication. PLoS Pathog 13:e1006674. https://doi.org/10.1371/journal.ppat.1006674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wang S-H, Wang K, Zhao K et al (2020) The Structure, Function, and Mechanisms of Action of Enterovirus Non-structural Protein 2C. Front Microbiol 11:615965. https://doi.org/10.3389/fmicb.2020.615965

    Article  PubMed  PubMed Central  Google Scholar 

  112. Wang L-C, Chen S-O, Chang S-P et al (2015) Enterovirus 71 Proteins 2A and 3D Antagonize the Antiviral Activity of Gamma Interferon via Signaling Attenuation. J Virol 89:7028–7037. https://doi.org/10.1128/JVI.00205-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Zheng Z, Li H, Zhang Z et al (2011) Enterovirus 71 2C protein inhibits TNF-α-mediated activation of NF-κB by suppressing IκB kinase β phosphorylation. J Immunol 187:2202–2212. https://doi.org/10.4049/jimmunol.1100285

    Article  CAS  PubMed  Google Scholar 

  114. Chang Z, Wang Y, Bian L et al (2017) Enterovirus 71 antagonizes the antiviral activity of host STAT3 and IL-6R with partial dependence on virus-induced miR-124. J Gen Virol 98:3008–3025. https://doi.org/10.1099/jgv.0.000967

    Article  CAS  PubMed  Google Scholar 

  115. Feng N, Zhou Z, Li Y et al (2017) Enterovirus 71-induced has-miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1. Virus Res 237:27–36. https://doi.org/10.1016/j.virusres.2017.05.008

    Article  CAS  PubMed  Google Scholar 

  116. Li M-L, Hsu T-A, Chen T-C et al (2002) The 3C Protease Activity of Enterovirus 71 Induces Human Neural Cell Apoptosis. Virology 293:386–395. https://doi.org/10.1006/viro.2001.1310

    Article  CAS  PubMed  Google Scholar 

  117. Chang S-C, Lin J-Y, Lo LY-C et al (2004) Diverse apoptotic pathways in enterovirus 71–infected cells. J Neurovirol 10:338–349. https://doi.org/10.1080/13550280490521032

    Article  CAS  PubMed  Google Scholar 

  118. Liang C-C, Sun M-J, Lei H-Y et al (2004) Human endothelial cell activation and apoptosis induced by enterovirus 71 infection. J Med Virol 74:597–603. https://doi.org/10.1002/jmv.20216

    Article  CAS  PubMed  Google Scholar 

  119. Chen L-C, Shyu H-W, Chen S-H et al (2006) Enterovirus 71 infection induces Fas ligand expression and apoptosis of Jurkat cells. J Med Virol 78:780–786. https://doi.org/10.1002/jmv.20623

    Article  CAS  PubMed  Google Scholar 

  120. Wang S, Lei H, Huang K et al (2003) Pathogenesis of Enterovirus 71 Brainstem Encephalitis in Pediatric Patients: Roles of Cytokines and Cellular Immune Activation in Patients with Pulmonary Edema. J INFECT DIS 188:564–570. https://doi.org/10.1086/376998

    Article  CAS  PubMed  Google Scholar 

  121. Chen T-C, Lai Y-K, Yu C-K, Juang J-L (2007) Enterovirus 71 triggering of neuronal apoptosis through activation of Abl-Cdk5 signalling. Cell Microbiol 9:2676–2688. https://doi.org/10.1111/j.1462-5822.2007.00988.x

    Article  CAS  PubMed  Google Scholar 

  122. Wang Y, Qin Y, Wang T et al (2018) Pyroptosis induced by enterovirus 71 and coxsackievirus B3 infection affects viral replication and host response. Sci Rep 8:2887. https://doi.org/10.1038/s41598-018-20958-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Chang L-Y (2004) Transmission and Clinical Features of Enterovirus 71 Infections in Household Contacts in Taiwan. JAMA 291:222. https://doi.org/10.1001/jama.291.2.222

    Article  CAS  PubMed  Google Scholar 

  124. Krishna M, Narang H (2008) The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci 65:3525–3544. https://doi.org/10.1007/s00018-008-8170-7

    Article  CAS  PubMed  Google Scholar 

  125. Polosa R, Sapsford RJ, Dokic D et al (2004) Induction of the epidermal growth factor receptor and its ligands in nasal epithelium by ozone. J Allergy Clin Immunol 113:120–126. https://doi.org/10.1016/j.jaci.2003.09.040

    Article  CAS  PubMed  Google Scholar 

  126. Yogarajah T, Ong KC, Perera D, Wong KT (2017) AIM2 Inflammasome-Mediated Pyroptosis in Enterovirus A71-Infected Neuronal Cells Restricts Viral Replication. Sci Rep 7:5845. https://doi.org/10.1038/s41598-017-05589-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wang W, **ao F, Wan P et al (2017) EV71 3D Protein Binds with NLRP3 and Enhances the Assembly of Inflammasome Complex. PLoS Pathog 13:e1006123. https://doi.org/10.1371/journal.ppat.1006123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Itsui Y, Sakamoto N, Kurosaki M et al (2006) Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication. J Viral Hepat 13:690–700. https://doi.org/10.1111/j.1365-2893.2006.00732.x

    Article  CAS  PubMed  Google Scholar 

  129. Long L, Wu L, Chen L et al (2021) Effect of early oxygen therapy and antiviral treatment on disease progression in patients with COVID-19: A retrospective study of medical charts in China. PLoS Negl Trop Dis 15:e0009051. https://doi.org/10.1371/journal.pntd.0009051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Li X-W, Ni X, Qian S-Y et al (2018) Chinese guidelines for the diagnosis and treatment of hand, foot and mouth disease (2018 edition). World J Pediatr 14:437–447. https://doi.org/10.1007/s12519-018-0189-8

    Article  PubMed  Google Scholar 

  131. Lin H, Huang L, Zhou J et al (2016) Efficacy and safety of interferon-α2b spray in the treatment of hand, foot, and mouth disease: a multicenter, randomized, double-blind trial. Arch Virol 161:3073–3080. https://doi.org/10.1007/s00705-016-3012-7

    Article  CAS  PubMed  Google Scholar 

  132. Tate PM, Mastrodomenico V, Mounce BC (2019) Ribavirin Induces Polyamine Depletion via Nucleotide Depletion to Limit Virus Replication. Cell Rep 28:2620–2633e4. https://doi.org/10.1016/j.celrep.2019.07.099

    Article  CAS  PubMed  Google Scholar 

  133. Noshy MM, Hussien NA, El-Ghor AA (2013) Evaluation of the role of the antioxidant silymarin in modulating the in vivo genotoxicity of the antiviral drug ribavirin in mice. Mutat Res 752:14–20. https://doi.org/10.1016/j.mrgentox.2012.12.012

    Article  CAS  PubMed  Google Scholar 

  134. Davoodi L, Masoum B, Moosazadeh M et al (2018) Psychiatric side effects of pegylated interferon–α and ribavirin therapy in Iranian patients with chronic hepatitis C: A meta–analysis. Exp Ther Med. https://doi.org/10.3892/etm.2018.6255

    Article  PubMed  PubMed Central  Google Scholar 

  135. Dieperink E, Ho SB, Thuras P, Willenbring ML (2003) A Prospective Study of Neuropsychiatric Symptoms Associated With Interferon-α-2b and Ribavirin Therapy for Patients With Chronic Hepatitis C. Psychosomatics 44:104–112. https://doi.org/10.1176/appi.psy.44.2.104

    Article  CAS  PubMed  Google Scholar 

  136. Predescu O, Streba LA-M, Irimia E et al (2012) Adverse effects of peg-Interferon and Ribavirin combined antiviral treatment in a Romanian hepatitis C virus infected cohort. Rom J Morphol Embryol 53:497–502

    CAS  PubMed  Google Scholar 

  137. Van Simaeys D, López-Colón D, Sefah K et al (2010) Study of the Molecular Recognition of Aptamers Selected through Ovarian Cancer Cell-SELEX. PLoS ONE 5:e13770. https://doi.org/10.1371/journal.pone.0013770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Tuerk C, Gold L (1990) Systematic Evolution of Ligands by Exponential Enrichment: RNA Ligands to Bacteriophage T4 DNA Polymerase. Science 249:505–510. https://doi.org/10.1126/science.2200121

    Article  CAS  PubMed  Google Scholar 

  139. Yang S, Wen J, Li H et al (2019) Aptamer-Engineered Natural Killer Cells for Cell-Specific Adaptive Immunotherapy. Small 15:e1900903. https://doi.org/10.1002/smll.201900903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Li W, Feng X, Yan X et al (2016) A DNA Aptamer Against Influenza A Virus: An Effective Inhibitor to the Hemagglutinin-Glycan Interactions. Nucleic Acid Ther 26:166–172. https://doi.org/10.1089/nat.2015.0564

    Article  CAS  PubMed  Google Scholar 

  141. Wen W, Qi Z, Wang J (2020) The Function and Mechanism of Enterovirus 71 (EV71) 3C Protease. Curr Microbiol 77:1968–1975. https://doi.org/10.1007/s00284-020-02082-4

    Article  CAS  PubMed  Google Scholar 

  142. Lu G, Qi J, Chen Z et al (2011) Enterovirus 71 and coxsackievirus A16 3C proteases: binding to rupintrivir and their substrates and anti-hand, foot, and mouth disease virus drug design. J Virol 85:10319–10331. https://doi.org/10.1128/JVI.00787-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Zhang X, Song Z, Qin B et al (2013) Rupintrivir is a promising candidate for treating severe cases of enterovirus-71 infection: evaluation of antiviral efficacy in a murine infection model. Antiviral Res 97:264–269. https://doi.org/10.1016/j.antiviral.2012.12.029

    Article  CAS  PubMed  Google Scholar 

  144. Zhang X-N, Song Z-G, Jiang T et al (2010) Rupintrivir is a promising candidate for treating severe cases of Enterovirus-71 infection. World J Gastroenterol 16:201–209. https://doi.org/10.3748/wjg.v16.i2.201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Tang Q, Xu Z, ** M et al (2020) Identification of dibucaine derivatives as novel potent enterovirus 2C helicase inhibitors: In vitro, in vivo, and combination therapy study. Eur J Med Chem 202:112310. https://doi.org/10.1016/j.ejmech.2020.112310

    Article  CAS  PubMed  Google Scholar 

  146. Fang Y, Wang C, Wang C et al (2021) Antiviral Peptides Targeting the Helicase Activity of Enterovirus Nonstructural Protein 2C. J Virol 95. https://doi.org/10.1128/JVI.02324-20

  147. Musharrafieh R, Kitamura N, Hu Y, Wang J (2020) Development of broad-spectrum enterovirus antivirals based on quinoline scaffold. Bioorg Chem 101:103981. https://doi.org/10.1016/j.bioorg.2020.103981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Liang Y, Zhou X, Yang E et al (2012) Analysis of the Th1/Th2 Reaction in the Immune Response Induced by EV71 Inactivated Vaccine in Neonatal Rhesus Monkeys. J Clin Immunol 32:1048–1058. https://doi.org/10.1007/s10875-012-9690-3

    Article  CAS  PubMed  Google Scholar 

  149. Liu L, Zhang Y, Wang J et al (2013) Study of the integrated immune response induced by an inactivated EV71 vaccine. PLoS ONE 8:e54451. https://doi.org/10.1371/journal.pone.0054451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Wu C-Y, Lin Y-W, Kuo C-H et al (2015) Inactivated Enterovirus 71 Vaccine Produced by 200-L Scale Serum-Free Microcarrier Bioreactor System Provides Cross-Protective Efficacy in Human SCARB2 Transgenic Mouse. PLoS ONE 10:e0136420. https://doi.org/10.1371/journal.pone.0136420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Cheng A, Fung C-P, Liu C-C et al (2013) A Phase I, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine. Vaccine 31:2471–2476. https://doi.org/10.1016/j.vaccine.2013.03.015

    Article  CAS  PubMed  Google Scholar 

  152. Tambyah PA, Oon J, Asli R et al (2019) An inactivated enterovirus 71 vaccine is safe and immunogenic in healthy adults: A phase I, double blind, randomized, placebo-controlled, study of two dosages. Vaccine 37:4344–4353. https://doi.org/10.1016/j.vaccine.2019.06.023

    Article  CAS  PubMed  Google Scholar 

  153. Zhang L, Gao F, Zeng G et al (2021) Immunogenicity and Safety of Inactivated Enterovirus 71 Vaccine in Children Aged 36–71 Months: A Double-Blind, Randomized, Controlled, Non-inferiority Phase III Trial. J Pediatr Infect Dis Soc 10:440–447. https://doi.org/10.1093/jpids/piaa129

    Article  CAS  Google Scholar 

  154. Wang Z, Zhou C, Gao F et al (2021) Preclinical evaluation of recombinant HFMD vaccine based on enterovirus 71 (EV71) virus-like particles (VLP): Immunogenicity, efficacy and toxicology. Vaccine 39:4296–4305. https://doi.org/10.1016/j.vaccine.2021.06.031

    Article  CAS  PubMed  Google Scholar 

  155. Zhang C, Ku Z, Liu Q et al (2015) High-yield production of recombinant virus-like particles of enterovirus 71 in Pichia pastoris and their protective efficacy against oral viral challenge in mice. Vaccine 33:2335–2341. https://doi.org/10.1016/j.vaccine.2015.03.034

    Article  CAS  PubMed  Google Scholar 

  156. Li H-Y, Han J-F, Qin C-F, Chen R (2013) Virus-like particles for enterovirus 71 produced from Saccharomyces cerevisiae potently elicits protective immune responses in mice. Vaccine 31:3281–3287. https://doi.org/10.1016/j.vaccine.2013.05.019

    Article  CAS  PubMed  Google Scholar 

  157. Kim Y-G, Lee Y, Kim JH et al (2020) Self-Assembled Multi-Epitope Peptide Amphiphiles Enhance the Immune Response against Enterovirus 71. Nanomaterials (Basel) 10:. https://doi.org/10.3390/nano10122342

  158. Andino R, Böddeker N, Silvera D, Gamarnik AV (1999) Intracellular determinants of picornavirus replication. Trends Microbiol 7:76–82. https://doi.org/10.1016/S0966-842X(98)01446-2

    Article  CAS  PubMed  Google Scholar 

  159. Li Z, Wang H, Chen Y et al (2017) Interleukin-18 protects mice from Enterovirus 71 infection. Cytokine 96:132–137. https://doi.org/10.1016/j.cyto.2017.04.002

    Article  CAS  PubMed  Google Scholar 

  160. Guo X, Zeng S, Ji X et al (2022) Type I Interferon-Induced TMEM106A Blocks Attachment of EV-A71 Virus by Interacting With the Membrane Protein SCARB2. Front Immunol 13:817835. https://doi.org/10.3389/fimmu.2022.817835

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Zhang H-P, Wang L, Qian J-H et al (2014) [Efficacy and safety of ribavirin aerosol in children with hand-foot-mouth disease]. Zhongguo Dang Dai Er Ke Za Zhi 16:272–276

    CAS  PubMed  Google Scholar 

  162. Pan S, Qian J, Gong X, Zhou Y (2014) [Effects of ribavirin aerosol on viral exclusion of patients with hand-foot-mouth disease]. Zhonghua Yi Xue Za Zhi 94:1563–1566

    PubMed  Google Scholar 

  163. Zhang W, Qiao H, Lv Y et al (2014) Apigenin inhibits enterovirus-71 infection by disrupting viral RNA association with trans-acting factors. PLoS ONE 9:e110429. https://doi.org/10.1371/journal.pone.0110429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors thank Professor Lingqing Xu from the Department of Qingyuan People’s Hospital, who carefully reviewed the manuscript and provided his expert opinion.

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Authors and Affiliations

  1. Academy of Pediatrics, Guangzhou Medical University, Guangzhou, China

    Jianmei Lai, Zhishan Li, Zifei Zhou, Chunhong Ma & Jiachun Guo

  2. The First People’s Hospital of Foshan, Foshan, China

    Lixin Pan

  3. The Sixth Clinical College, Guangzhou Medical University, Guangzhou, China

    Yunxia Huang

  4. Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China

    Lingqing Xu

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Jianmei Lai and Zhishan Li designed the study and drafted the manuscript. Lixin Pan and Chunhong Ma collected data. Yunxia Huang and Jiachun Guo analyzed the data. Jianmei Lai, Zhishan Li, and Zifei Zhou refined the manuscript and coordination. All authors read and approved the final manuscript.

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Correspondence to Lingqing Xu.

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Lai, J., Li, Z., Pan, L. et al. Research progress on pathogenic and therapeutic mechanisms of Enterovirus A71. Arch Virol 168, 260 (2023). https://doi.org/10.1007/s00705-023-05882-8

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