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Pathogen–Host Interaction and Its Associated Molecular Mechanism in HFMD Pathology and Immunology

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Molecular Biology of Hand-Foot-Mouth Diseases

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Abstract

Hand, foot, and mouth disease (HFMD) is caused by the enterovirus family, which includes EV-A71 and more than 10 other members. The disease involves a complex pathological mechanism that includes intricate and finely-tuned interactions between these pathogens and the host. The research on vaccines that can effectively be used to prevent HFMD caused by major pathogens suggested that the viruses presenting with the same structure but different antigenic traits in response to the immune system interactions enable to interact dynamically to cell surface receptors and to lead to similar pathological outcome through diverse mechanisms. This suggests that further understanding of the whole process of signal stimulation by viral antigen molecules and innate immune receptor molecules could improve our recognition about the events of pathological injury to the body and the characterization of antiviral immune responses with phenotypic differences during the pathogenesis. The accumulated data about process of interaction between virus structure and host in molecular level might provide the theoretical and technical support for next generation of vaccine against HFMD for public health initiatives.

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References

  1. Gu J, Wu J, Cao Y, Zou X, Jia X, Yin Y, et al. A mouse model for infection with enterovirus A71 in small extracellular vesicles. mSphere. 2020;5(4):e00377–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Sun J, Li H, Sun B. Correlation analysis on serum inflammatory cytokine level and neurogenic pulmonary edema for children with severe hand-foot-mouth disease. Eur J Med Res. 2018;23(1):21.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Rosenfeld AB, Shen EQL, Melendez M, Mishra N, Lipkin WI, Racaniello VR. Cross-reactive antibody responses against nonpoliovirus enteroviruses. MBio. 2022;13:e0366021.

    Article  PubMed  Google Scholar 

  4. Li Q, Wang Y, Xue W, Bian Z, Gao Y, Zeng Y, et al. Immunomodulatory effects of platelets on the severity of hand, foot, and mouth disease infected with enterovirus 71. Pediatr Res. 2021;89(4):814–22.

    Article  CAS  PubMed  Google Scholar 

  5. Peng L, Luo R, Jiang Z. Risk factors for neurogenic pulmonary edema in patients with severe hand, foot, and mouth disease: a meta-analysis. Int J Infect Dis. 2017;65:37–43.

    Article  PubMed  Google Scholar 

  6. Tamura K, Kohnoe M, Takashino A, Kobayashi K, Koike S, Karwal L, et al. TAK - 021, an inactivated Enterovirus 71 vaccine candidate, provides cross-protection against heterologous sub-genogroups in human scavenger receptor B2 transgenic mice. Vaccine. 2022;40(24):3330–7.

    Article  CAS  PubMed  Google Scholar 

  7. Kinobe R, Wiyatno A, Artika IM, Safari D. Insight into the enterovirus A71: a review. Rev Med Virol. 2022;32:e2361.

    Article  CAS  PubMed  Google Scholar 

  8. George GM, Darius-J Daniel H, Mathew L, Peter D, George L, Pulimood S, et al. Changing epidemiology of human enteroviruses (HEV) in a hand, foot and mouth disease outbreak in Vellore, south India. Indian J Med Microbiol. 2022;40(3):394–8.

    Article  CAS  PubMed  Google Scholar 

  9. Liu L, Wang M, Yu R, Li H, Fan J, Yan J, et al. Preparation and verification of a monoclonal antibody against a conserved linear epitope in enterovirus A protein 2C. J Virol Methods. 2021;298:114298.

    Article  CAS  PubMed  Google Scholar 

  10. Dong Y, Wan Z, Li S, Wang J, Jin X, Yu G, et al. Genomic phylogenetic analyses of four major hand, foot and mouth disease-related enteroviruses. Acta Virol. 2022;66(1):27–38.

    Article  CAS  PubMed  Google Scholar 

  11. Bian L, Gao F, Mao Q, Sun S, Wu X, Liu S, et al. Hand, foot, and mouth disease associated with coxsackievirus A10: more serious than it seems. Expert Rev Anti-Infect Ther. 2019;17(4):233–42.

    Article  CAS  PubMed  Google Scholar 

  12. Mao Q, Wang Y, Bian L, Xu M, Liang Z. EV-A71 vaccine licensure: a first step for multivalent enterovirus vaccine to control HFMD and other severe diseases. Emerg Microbes Infect. 2016;5(7):e75.

    PubMed  PubMed Central  Google Scholar 

  13. Yang Q, Yan D, Song Y, Zhu S, He Y, Han Z, et al. Whole-genome analysis of coxsackievirus B3 reflects its genetic diversity in China and worldwide. Virol J. 2022;19(1):69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yan X, Zhang Z, Yang Z, Zhu C, Hu Y, Liu Q. Clinical and etiological characteristics of atypical hand-foot-and-mouth disease in children from Chongqing, China: a retrospective study. Biomed Res Int. 2015;2015:802046.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li J, Zhu R, Huo D, Du Y, Yan Y, Liang Z, et al. An outbreak of Coxsackievirus A6-associated hand, foot, and mouth disease in a kindergarten in Beijing in 2015. BMC Pediatr. 2018;18(1):277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xu N, Yang J, Zheng B, Zhang Y, Cao Y, Huan C, et al. The pyrimidine analog FNC potently inhibits the replication of multiple enteroviruses. J Virol. 2020;94(9):e00204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gonzalez G, Carr MJ, Kobayashi M, Hanaoka N, Fujimoto T. Enterovirus-associated hand-foot and mouth disease and neurological complications in Japan and the rest of the world. Int J Mol Sci. 2019;20(20):E5201.

    Article  Google Scholar 

  18. Zhang Y, Yang E, Pu J, Liu L, Che Y, Wang J, et al. The gene expression profile of peripheral blood mononuclear cells from EV71-infected rhesus infants and the significance in viral pathogenesis. PLoS One. 2014;9(1):e83766.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Song J, Hu Y, Hu Y, Wang J, Zhang X, Wang L, et al. Global gene expression analysis of peripheral blood mononuclear cells in rhesus monkey infants with CA16 infection-induced HFMD. Virus Res. 2016;214:1–10.

    Article  CAS  PubMed  Google Scholar 

  20. Hu Y, Song J, Liu L, Li J, Tang B, Zhang Y, et al. Comparison analysis of microRNAs in response to EV71 and CA16 infection in human bronchial epithelial cells by high-throughput sequencing to reveal differential infective mechanisms. Virus Res. 2017;228:90–101.

    Article  CAS  PubMed  Google Scholar 

  21. Chapman MS, Rossmann MG. Comparison of surface properties of picornaviruses: strategies for hiding the receptor site from immune surveillance. Virology. 1993;195(2):745–56.

    Article  CAS  PubMed  Google Scholar 

  22. Guo D, Yu X, Wang D, Li Z, Zhou Y, Xu G, et al. SLC35B2 acts in a dual role in the host sulfation required for EV71 infection. J Virol. 2022;96(9):e0204221.

    Article  PubMed  Google Scholar 

  23. Yamayoshi S, Fujii K, Koike S. Receptors for enterovirus 71. Emerg Microbes Infect. 2014;3(7):e53.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Feng T, Zhang J, Chen Z, Pan W, Chen Z, Yan Y, et al. Glycosylation of viral proteins: implication in virus-host interaction and virulence. Virulence. 2022;13(1):670–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Connolly SA, Jardetzky TS, Longnecker R. The structural basis of herpesvirus entry. Nat Rev Microbiol. 2021;19(2):110–21.

    Article  CAS  PubMed  Google Scholar 

  26. Baggen J, Thibaut HJ, Strating JRPM, van Kuppeveld FJM. The life cycle of non-polio enteroviruses and how to target it. Nat Rev Microbiol. 2018;16(6):368–81.

    Article  CAS  PubMed  Google Scholar 

  27. Yuan S, Li G, Wang Y, Gao Q, Wang Y, Cui R, et al. Identification of positively charged residues in enterovirus 71 capsid protein VP1 essential for production of infectious particles. J Virol. 2016;90(2):741–52.

    Article  CAS  PubMed  Google Scholar 

  28. McLeish NJ, Williams ÇH, Kaloudas D, Roivainen MM, Stanway G. Symmetry-related clustering of positive charges is a common mechanism for heparan sulfate binding in enteroviruses. J Virol. 2012;86(20):11163–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhu L, Sun Y, Fan J, Zhu B, Cao L, Gao Q, et al. Structures of Coxsackievirus A10 unveil the molecular mechanisms of receptor binding and viral uncoating. Nat Commun. 2018;9(1):4985.

    Article  PubMed  PubMed Central  Google Scholar 

  30. De Colibus L, Wang X, Tijsma A, Neyts J, Spyrou JA, Ren J, et al. Structure elucidation of coxsackievirus A16 in complex with GPP3 informs a systematic review of highly potent capsid binders to enteroviruses. PLoS Pathog. 2015;11(10):e1005165.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Xiao C, Bator-Kelly CM, Rieder E, Chipman PR, Craig A, Kuhn RJ, et al. The crystal structure of coxsackievirus A21 and its interaction with ICAM-1. Struct Lond Engl. 2005;13(7):1019–33.

    CAS  Google Scholar 

  32. Liu Y, Sheng J, Fokine A, Meng G, Shin WH, Long F, et al. Structure and inhibition of EV-D68, a virus that causes respiratory illness in children. Science. 2015;347(6217):71–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lyu K, He Y, Li H, Chen R. Crystal structures of yeast-produced enterovirus 71 and enterovirus 71/coxsackievirus A16 chimeric virus-like particles provide the structural basis for novel vaccine design against hand-foot-and-mouth disease. J Virol. 2015;89(12):6196–208.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shah PNM, Filman DJ, Karunatilaka KS, Hesketh EL, Groppelli E, Strauss M, et al. Cryo-EM structures reveal two distinct conformational states in a picornavirus cell entry intermediate. PLoS Pathog. 2020;16(9):e1008920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Strauss M, Filman DJ, Belnap DM, Cheng N, Noel RT, Hogle JM. Nectin-like interactions between poliovirus and its receptor trigger conformational changes associated with cell entry. J Virol. 2015;89(8):4143–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Racaniello VR. Early events in poliovirus infection: virus-receptor interactions. Proc Natl Acad Sci U S A. 1996;93(21):11378–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Racaniello VR. The poliovirus receptor: a hook, or an unzipper? Struct Lond Engl. 1996;4(7):769–73.

    CAS  Google Scholar 

  38. Belnap DM, Filman DJ, Trus BL, Cheng N, Booy FP, Conway JF, et al. Molecular tectonic model of virus structural transitions: the putative cell entry states of poliovirus. J Virol. 2000;74(3):1342–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wien MW, Chow M, Hogle JM. Poliovirus: new insights from an old paradigm. Structure. 1996;4(7):763–7.

    Article  CAS  PubMed  Google Scholar 

  40. Jurgeit A, McDowell R, Moese S, Meldrum E, Schwendener R, Greber UF. Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects. PLoS Pathog. 2012;8(10):e1002976.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dun Y, Yan J, Wang M, Wang M, Liu L, Yu R, et al. Rac1-dependent endocytosis and Rab5-dependent intracellular trafficking are required by Enterovirus A71 and Coxsackievirus A10 to establish infections. Biochem Biophys Res Commun. 2020;529(1):97–103.

    Article  PubMed  Google Scholar 

  42. Yamayoshi S, Ohka S, Fujii K, Koike S. Functional comparison of SCARB2 and PSGL1 as receptors for enterovirus 71. J Virol. 2013;87(6):3335–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yamayoshi S, Yamashita Y, Li J, Hanagata N, Minowa T, Takemura T, et al. Scavenger receptor B2 is a cellular receptor for enterovirus 71. Nat Med. 2009;15(7):798–801.

    Article  CAS  PubMed  Google Scholar 

  44. Patel KP, Bergelson JM. Receptors identified for hand, foot and mouth virus. Nat Med. 2009;15(7):728–9.

    Article  CAS  PubMed  Google Scholar 

  45. Nishimura Y, Shimizu H. Cellular receptors for human enterovirus species a. Front Microbiol. 2012;3:105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cui Y, Peng R, Song H, Tong Z, Qu X, Liu S, et al. Molecular basis of Coxsackievirus A10 entry using the two-in-one attachment and uncoating receptor KRM1. Proc Natl Acad Sci U S A. 2020;117(31):18711–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhao Y, Zhou D, Ni T, Karia D, Kotecha A, Wang X, et al. Hand-foot-and-mouth disease virus receptor KREMEN1 binds the canyon of Coxsackie Virus A10. Nat Commun. 2020;11(1):38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Staring J, van den Hengel LG, Raaben M, Blomen VA, Carette JE, Brummelkamp TR. KREMEN1 is a host entry receptor for a major group of enteroviruses. Cell Host Microbe. 2018;23(5):636–43.

    Article  CAS  PubMed  Google Scholar 

  49. Nishimura Y, Shimojima M, Tano Y, Miyamura T, Wakita T, Shimizu H. Human P-selectin glycoprotein ligand-1 is a functional receptor for enterovirus 71. Nat Med. 2009;15(7):794–7.

    Article  CAS  PubMed  Google Scholar 

  50. Nishimura Y, Lee H, Hafenstein S, Kataoka C, Wakita T, Bergelson JM, et al. Enterovirus 71 binding to PSGL-1 on leukocytes: VP1-145 acts as a molecular switch to control receptor interaction. PLoS Pathog. 2013;9(7):e1003511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhou D, Zhao Y, Kotecha A, Fry EE, Kelly JT, Wang X, et al. Unexpected mode of engagement between enterovirus 71 and its receptor SCARB2. Nat Microbiol. 2019 Mar;4(3):414–9.

    Article  CAS  PubMed  Google Scholar 

  52. Dang M, Wang X, Wang Q, Wang Y, Lin J, Sun Y, et al. Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71. Protein Cell. 2014;5(9):692–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Calvo D, Dopazo J, Vega MA. The CD36, CLA-1 (CD36L1), and LIMPII (CD36L2) gene family: cellular distribution, chromosomal location, and genetic evolution. Genomics. 1995;25(1):100–6.

    Article  CAS  PubMed  Google Scholar 

  54. Tinoco R, Otero DC, Takahashi AA, Bradley LM. PSGL-1: a new player in the immune checkpoint landscape. Trends Immunol. 2017;38(5):323–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zebisch M, Jackson VA, Zhao Y, Jones EY. Structure of the dual-mode WNT regulator Kremen1 and insight into ternary complex formation with LRP6 and dickkopf. Struct Lond Engl. 2016;24(9):1599–605.

    CAS  Google Scholar 

  56. Zhu Z, Gershon MD, Ambron R, Gabel C, Gershon AA. Infection of cells by varicella zoster virus: inhibition of viral entry by mannose 6-phosphate and heparin. Proc Natl Acad Sci U S A. 1995;92(8):3546–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gerlt V, Mayr J, Del Sarto J, Ludwig S, Boergeling Y. Cellular protein phosphatase 2A regulates cell survival mechanisms in influenza A virus infection. Int J Mol Sci. 2021;22(20):11164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zhu Y, Hu M, Ngowo J, Gao X, Chen X, Yan H, et al. Deacetylation of BmAda3 is required for cell apoptosis caused by Bombyx mori nucleopolyhedrovirus infection. Arch Insect Biochem Physiol. 2021;108(2):e21838.

    Article  CAS  PubMed  Google Scholar 

  59. Zhang Y, Li M, Li L, Qian G, Wang Y, Chen Z, et al. β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion. Nat Commun. 2020;11(1):6000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Jin Y, Zhang R, Wu W, Duan G. Innate immunity evasion by enteroviruses linked to epidemic hand-foot-mouth disease. Front Microbiol. 2018;9:2422.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Zhang W, Zhang L, Wu Z, Tien P. Differential interferon pathway gene expression patterns in Rhabdomyosarcoma cells during enterovirus 71 or coxsackievirus A16 infection. Biochem Biophys Res Commun. 2014;447(3):550–5.

    Article  CAS  PubMed  Google Scholar 

  62. Fu Y, Zhang L, Zhang F, Tang T, Zhou Q, Feng C, et al. Exosome-mediated miR-146a transfer suppresses type I interferon response and facilitates EV71 infection. PLoS Pathog. 2017;13(9):e1006611.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Chen N, Li X, Li P, Pan Z, Ding Y, Zou D, et al. Enterovirus 71 inhibits cellular type I interferon signaling by inhibiting host RIG-I ubiquitination. Microb Pathog. 2016;100:84–9.

    Article  CAS  PubMed  Google Scholar 

  64. Lei X, Liu X, Ma Y, Sun Z, Yang Y, Jin Q, et al. The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses. J Virol. 2010;84(16):8051–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lei X, Sun Z, Liu X, Jin Q, He B, Wang J. Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3. J Virol. 2011;85(17):8811–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Lei X, Xiao X, Xue Q, Jin Q, He B, Wang J. Cleavage of interferon regulatory factor 7 by enterovirus 71 3C suppresses cellular responses. J Virol. 2013;87(3):1690–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Barral PM, Sarkar D, Fisher PB, Racaniello VR. RIG-I is cleaved during picornavirus infection. Virology. 2009;391(2):171–6.

    Article  CAS  PubMed  Google Scholar 

  68. Chen B, Wang Y, Pei X, Wang S, Zhang H, Peng Y. Cellular caspase-3 contributes to EV-A71 2Apro-mediated down-regulation of IFNAR1 at the translation level. Virol Sin. 2020;35(1):64–72.

    Article  CAS  PubMed  Google Scholar 

  69. Lu J, Yi L, Zhao J, Yu J, Chen Y, Lin M, et al. Enterovirus 71 disrupts interferon signaling by reducing the level of interferon receptor 1. J Virol. 2012;86(7):3767–76.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Kastan JP, Tremblay MW, Brown MC, Trimarco JD, Dobrikova EY, Dobrikov MI, et al. Enterovirus 2Apro cleavage of the YTHDF m6A readers implicates YTHDF3 as a mediator of Type I interferon-driven JAK/STAT signaling. MBio. 2021;12(2):e00116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wang C, Sun M, Yuan X, Ji L, Jin Y, Cardona CJ, et al. Enterovirus 71 suppresses interferon responses by blocking Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling through inducing karyopherin-α1 degradation. J Biol Chem. 2017;292(24):10262–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Liu Y, Zhang Z, Zhao X, Yu R, Zhang X, Wu S, et al. Enterovirus 71 inhibits cellular type I interferon signaling by downregulating JAK1 protein expression. Viral Immunol. 2014;27(6):267–76.

    Article  CAS  PubMed  Google Scholar 

  73. Lv X, Qiu M, Chen D, Zheng N, Jin Y, Wu Z. Apigenin inhibits enterovirus 71 replication through suppressing viral IRES activity and modulating cellular JNK pathway. Antivir Res. 2014;109:30–41.

    Article  CAS  PubMed  Google Scholar 

  74. Wang H, Yuan M, Wang S, Zhang L, Zhang R, Zou X, et al. STAT3 regulates the type I IFN-mediated antiviral response by interfering with the nuclear entry of STAT1. Int J Mol Sci. 2019;20(19):E4870.

    Article  Google Scholar 

  75. Yamayoshi S, Iizuka S, Yamashita T, Minagawa H, Mizuta K, Okamoto M, et al. Human SCARB2-dependent infection by coxsackievirus A7, A14, and A16 and enterovirus 71. J Virol. 2012;86(10):5686–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hu Y, Song J, Tang B, Li J, Liu LD, Wang LC, et al. Comparative analysis of IFN-I production and Th differentiation related molecules subjected to EV71 and CA16 infections in CD1c+ DC from rhesus monkey. Chin J Microbiol Immunol. 2017;37(1):34–42.

    Google Scholar 

  77. Li H, Bai Z, Li C, Sheng C, Zhao X. EV71 infection induces cell apoptosis through ROS generation and SIRT1 activation. J Cell Biochem. 2020;121(10):4321–31.

    Article  CAS  PubMed  Google Scholar 

  78. Ho HY, Cheng ML, Weng SF, Leu YL, Chiu DTY. Antiviral effect of epigallocatechin gallate on enterovirus 71. J Agric Food Chem. 2009;57(14):6140–7.

    Article  CAS  PubMed  Google Scholar 

  79. Tung WH, Hsieh HL, Lee IT, Yang CM. Enterovirus 71 induces integrin β1/EGFR-Rac1-dependent oxidative stress in SK-N-SH cells: role of HO-1/CO in viral replication. J Cell Physiol. 2011;226(12):3316–29.

    Article  CAS  PubMed  Google Scholar 

  80. Cheng ML, Weng SF, Kuo CH, Ho HY. Enterovirus 71 induces mitochondrial reactive oxygen species generation that is required for efficient replication. PLoS One. 2014;9(11):e113234.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Chen SG, Leu YL, Cheng ML, Ting SC, Liu CC, Wang SD, et al. Anti-enterovirus 71 activities of Melissa officinalis extract and its biologically active constituent rosmarinic acid. Sci Rep. 2017;7(1):12264.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Chen S, Cheng M, Chen K, Horng J, Liu C, Wang S, et al. Antiviral activities of Schizonepeta tenuifolia Briq. against enterovirus 71 in vitro and in vivo. Sci Rep. 2017;7(1):935.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Chen D, Tian X, Zou X, Xu S, Wang H, Zheng N, et al. Harmine, a small molecule derived from natural sources, inhibits enterovirus 71 replication by targeting NF-κB pathway. Int Immunopharmacol. 2018;60:111–20.

    Article  CAS  PubMed  Google Scholar 

  84. Qin Y, Lin L, Chen Y, Wu S, Si X, Wu H, et al. Curcumin inhibits the replication of enterovirus 71 in vitro. Acta Pharm Sin B. 2014;4(4):284–94.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Lei X, Han N, Xiao X, Jin Q, He B, Wang J. Enterovirus 71 3C inhibits cytokine expression through cleavage of the TAK1/TAB1/TAB2/TAB3 complex. J Virol. 2014;88(17):9830–41.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Li Y, Liu C, Deng H, Wang M, Tian Y, Chen Y, et al. DNA methylation and single-nucleotide polymorphisms in DDX58 are associated with hand, foot and mouth disease caused by enterovirus 71. PLoS Negl Trop Dis. 2022;16(1):e0010090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Xiao H, Li J, Yang X, Li Z, Wang Y, Rui Y, et al. Ectopic expression of TRIM25 restores RIG-I expression and IFN production reduced by multiple enteroviruses 3Cpro. Virol Sin. 2021;36(6):1363–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Zhang R, Cheng M, Liu B, Yuan M, Chen D, Wang Y, et al. DEAD-box helicase DDX6 facilitated RIG-I-mediated type-I interferon response to EV71 infection. Front Cell Infect Microbiol. 2021;11:725392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Yang W, Li D, Ru Y, Bai J, Ren J, Zhang J, et al. Foot-and-mouth disease virus 3A protein causes upregulation of autophagy-related protein LRRC25 To inhibit the G3BP1-mediated RIG-like helicase-signaling pathway. J Virol. 2020;94(8):e02086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang B, Xi X, Lei X, Zhang X, Cui S, Wang J, et al. Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses. PLoS Pathog. 2013;9(3):e1003231.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Cao Z, Zhou Y, Zhu S, Feng J, Chen X, Liu S, et al. Pyruvate carboxylase activates the RIG-I-like receptor-mediated antiviral immune response by targeting the MAVS signalosome. Sci Rep. 2016;6:22002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Song J, Hu Y, Li J, Zheng H, Wang J, Guo L, et al. 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. 2018;163(1):135–44.

    Article  CAS  PubMed  Google Scholar 

  93. Wang C, Ji L, Yuan X, Jin Y, Cardona CJ, Xing Z. Differential regulation of tlr signaling on the induction of antiviral interferons in human intestinal epithelial cells infected with enterovirus 71. PLoS One. 2016;11(3):e0152177.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Wang W, Xiao F, Wan P, Pan P, Zhang Y, Liu F, et al. EV71 3D protein binds with NLRP3 and enhances the assembly of inflammasome complex. PLoS Pathog. 2017;13(1):e1006123.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Wang H, Lei X, Xiao X, Yang C, Lu W, Huang Z, et al. Reciprocal regulation between enterovirus 71 and the NLRP3 inflammasome. Cell Rep. 2015;12(1):42–8.

    Article  CAS  PubMed  Google Scholar 

  96. Li H, Zhang Y, Wang L, Jiang L, Fan S, Jiang E, et al. Effect of VP1 proteins of enterovirus 71 and coxsakievirus A 16 on expression of natural immunity-associated signaling molecules and immune response of T cells in human bronchial epithelial cells. Chin J Biol Prod. 2019;32(3):255–64.

    Google Scholar 

  97. Zhao T, Zhang Z, Zhang Y, Feng M, Fan S, Wang L, et al. Dynamic interaction of enterovirus 71 and dendritic cells in infected neonatal rhesus macaques. Front Cell Infect Microbiol. 2017;7:171.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Fan S, Liao Y, Lian Y, Jiang G, Jiang L, Dong C, et al. Role of innate lymphoid cells and dendritic cells in intradermal immunization of the enterovirus antigen. NPJ Vaccines. 2019;4:14.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Lin Y, Wang S, Tung Y, Chen S. Enterovirus 71 infection of human dendritic cells. Exp Biol Med. 2009;234(10):1166–73.

    Article  CAS  Google Scholar 

  100. Song J, Hu Y, Zheng H, Guo L, Huang X, Jiang X, et al. Comparative analysis of putative novel microRNA expression profiles induced by enterovirus 71 and coxsackievirus A16 infections in human umbilical vein endothelial cells using high-throughput sequencing. Infect Genet Evol J Mol Epidemiol Evol Genet Infect Dis. 2019;73:401–10.

    CAS  Google Scholar 

  101. Feng M, Guo S, Fan S, Zeng X, Zhang Y, Liao Y, et al. The preferential infection of astrocytes by enterovirus 71 plays a key role in the viral neurogenic pathogenesis. Front Cell Infect Microbiol. 2016;6:192.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Hooi YT, Ong KC, Tan SH, Perera D, Wong KT. A novel orally infected hamster model for Coxsackievirus A16 hand-foot-and-mouth disease and encephalomyelitis. Lab Investig J Tech Methods Pathol. 2020;100(9):1262–75.

    Article  CAS  Google Scholar 

  103. Tikute SS, Wangikar PB, Varanasi G. Pathological and molecular studies on Coxsackie virus A-16 isolated from hand, foot, and mouth disease cases in India: approach using neonatal mouse model. J Med Virol. 2019;91(10):1765–75.

    Article  CAS  PubMed  Google Scholar 

  104. Wang J, Zhang Y, Zhang X, Hu Y, Dong C, Liu L, et al. Pathologic and immunologic characteristics of coxsackievirus A16 infection in rhesus macaques. Virology. 2017;500:198–208.

    Article  CAS  PubMed  Google Scholar 

  105. Wang J, Li W, Zhao H, Liu L, Tang D, Yang L, et al. Biological characteristics related to the transmission of entero virus 71 in neonatal rhesus monkeys. J Microbes Infect. 2011;6(3):133–8.

    Google Scholar 

  106. Connor RI, Brickley EB, Wieland-Alter WF, Ackerman ME, Weiner JA, Modlin JF, et al. Mucosal immunity to poliovirus. Mucosal Immunol. 2022;15(1):1–9.

    Article  CAS  PubMed  Google Scholar 

  107. Embree J, Law B, Voloshen T, Tomovici A. Immunogenicity, safety, and antibody persistence at 3, 5, and 10 years postvaccination in adolescents randomized to booster immunization with a combined tetanus, diphtheria, 5-component acellular pertussis, and inactivated poliomyelitis vaccine administered with a hepatitis B virus vaccine concurrently or 1 month apart. Clin Vaccine Immunol. 2015;22(3):282–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Urueña A, Badano MN, Baré P, González J, Vicentín R, Calli R, et al. Humoral and cellular immune memory response 12 years following single dose vaccination against hepatitis A in Argentinian children. Vaccine. 2022;40(1):114–21.

    Article  PubMed  Google Scholar 

  109. Vizzotti C, González J, Rearte A, Urueña A, Pérez Carrega M, Calli R, et al. Single-dose universal hepatitis A immunization in Argentina: low viral circulation and high persistence of protective antibodies up to 4 years. J Pediatr Infect Dis Soc. 2015;4(4):e62–7.

    Article  CAS  Google Scholar 

  110. Urueña A, González JE, Rearte A, Pérez Carrega ME, Calli R, Pagani MF, et al. Single-dose universal Hepatitis A immunization in one-year-old children in Argentina: high prevalence of protective antibodies up to 9 years after vaccination. Pediatr Infect Dis J. 2016;35(12):1339–42.

    Article  PubMed  Google Scholar 

  111. Opare JK, Akweongo P, Afari EA, Odoom JK. Poliovirus neutralizing antibody levels among individuals in three regions of Ghana. Ghana Med J. 2019;53(2):170–80.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Liu L, Mo Z, Liang Z, Zhang Y, Li R, Ong KC, et al. Immunity and clinical efficacy of an inactivated enterovirus 71 vaccine in healthy Chinese children: a report of further observations. BMC Med. 2015;13:226.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Dias E, Dias M. Recurring hand foot mouth disease in a child. Ann Trop Med Public Health. 2012;5:40–1. https://doi.org/10.4103/1755-6783.

    Article  Google Scholar 

  114. Huang J, Liao Q, Ooi MH, Cowling BJ, Chang Z, Wu P, et al. Epidemiology of recurrent hand, foot and mouth disease, China, 2008-2015. Emerg Infect Dis. 2018;24(3):432–42.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Sutton-Hayes S, Weisse ME, Wilson NW, Ogershok PR. A recurrent presentation of hand, foot, and mouth disease. Clin Pediatr. 2006;45(4):373–6.

    Article  Google Scholar 

  116. Hamberg U, Syvanen AC, Karkkainen T. Human kininogen from Cohn’s fraction IV: comparisons of antigenicity and multiple forms. Adv Exp Med Biol. 1979;120B:173–83.

    CAS  PubMed  Google Scholar 

  117. Saxena VK, Pawar SD, Qureshi THIH, Surve P, Yadav P, Nabi F, et al. Isolation and molecular characterization of coxsackievirus A6 and coxsackievirus A16 from a case of recurrent hand, foot and mouth disease in Mumbai, Maharashtra, India, 2018. Virus Dis. 2020;31(1):56–60.

    Article  CAS  Google Scholar 

  118. Zhu R, Cheng T, Yin Z, Liu D, Xu L, Li Y, et al. Serological survey of neutralizing antibodies to eight major enteroviruses among healthy population. Emerg Microbes Infect. 2018;7(1):2.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Kim S, Bae KS, Kim JH, Kang JH, Choi UY. Seroprevalence of neutralizing antibodies against candidate serotypes of enterovirus vaccines among Korean children. Viral Immunol. 2021;34(2):62–7.

    Article  CAS  PubMed  Google Scholar 

  120. Zhu Z, Zhu S, Guo X, Wang J, Wang D, Yan D, et al. Retrospective seroepidemiology indicated that human enterovirus 71 and coxsackievirus A16 circulated wildly in central and southern China before large-scale outbreaks from 2008. Virol J. 2010;7:300.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Yang Z, Zhu S, Zhu H, An H, Mao N, Ji Y, et al. Seroepidemical study of coxsackievirus A 16, in four provinces, China, 2005. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2009;23(2):103–5.

    PubMed  Google Scholar 

  122. Fan S, Liao Y, Jiang G, Jiang L, Wang L, Xu X, et al. Study of integrated protective immunity induced in rhesus macaques by the intradermal administration of a bivalent EV71-CA16 inactivated vaccine. Vaccine. 2020;38(8):2034–44.

    Article  CAS  PubMed  Google Scholar 

  123. Fan S, Liao Y, Jiang G, Wang L, Zhao H, Yu L, et al. Efficacy of an inactivated bivalent vaccine for enterovirus 71 and coxsackievirus A16 in mice immunized intradermally. Vaccine. 2021;39(3):596–604.

    Article  CAS  PubMed  Google Scholar 

  124. Dong C, Wang J, Liu L, Zhao H, Shi H, Zhang Y, et al. Optimized development of a candidate strain of inactivated EV71 vaccine and analysis of its immunogenicity in rhesus monkeys. Hum Vaccin. 2010;6(12):1028–37.

    Article  CAS  PubMed  Google Scholar 

  125. Dong C, Liu L, Zhao H, Wang J, Liao Y, Zhang X, et al. Immunoprotection elicited by an enterovirus type 71 experimental inactivated vaccine in mice and rhesus monkeys. Vaccine. 2011;29(37):6269–75.

    Article  CAS  PubMed  Google Scholar 

  126. Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med. 2014;370(9):829–37.

    Article  CAS  PubMed  Google Scholar 

  127. Wei M, Meng F, Wang S, Li J, Zhang Y, Mao Q, et al. 2-year efficacy, immunogenicity, and safety of vigoo enterovirus 71 vaccine in healthy Chinese children: a randomized open-label study. J Infect Dis. 2017;215(1):56–63.

    Article  CAS  PubMed  Google Scholar 

  128. Nguyen TT, Chiu CH, Lin CY, Chiu NC, Chen PY, Le TTV, et al. Efficacy, safety, and immunogenicity of an inactivated, adjuvanted enterovirus 71 vaccine in infants and children: a multiregion, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Lond Engl. 2022;399(10336):1708–17.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Yunnan Key Laboratory of Vaccine Research and Development on Severe Infectious Diseases, Kunming, China

    Qihan Li, Ying Zhang & Yun Liao

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  1. Qihan Li
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  2. Ying Zhang
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  1. Department of Viral Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan, China

    Xingli Xu

  2. Vaccine CLINICAL Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan, China

    Yanchun Che

  3. Department of Viral Immunology, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan, China

    Qihan Li

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Li, Q., Zhang, Y., Liao, Y. (2024). Pathogen–Host Interaction and Its Associated Molecular Mechanism in HFMD Pathology and Immunology. In: Xu, X., Che, Y., Li, Q. (eds) Molecular Biology of Hand-Foot-Mouth Diseases. Springer, Singapore. https://doi.org/10.1007/978-981-99-9660-5_5

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