Polymorphisms in the DC-SIGN gene and their association with the severity of hand, foot, and mouth disease caused by enterovirus 71


Severe hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) infection is associated with high mortality and disability. DC-SIGN, a receptor for EV71, is widely distributed in dendritic cells and may influence the severity of HFMD caused by EV71 infection. This observational study attempts to explore whether single-nucleotide polymorphisms (SNPs) in DC-SIGN are related to the severity of EV71-associated HFMD. Based on linkage disequilibrium and functional predictions, two DC-SIGN SNPs were selected and tested to explore their potential association with the severity of HFMD caused by EV71 infection. Two hundred sixteen Han Chinese children with HFMD caused by EV71 were enrolled to obtain clinical data, including the severity of HFMD, serum DC-SIGN levels, and DC-SIGN SNPs. We found a significant association between the rs7248637 polymorphism (A vs. G: OR = 0.644, 95% CI = 0.515-0.806) and the severity of HFMD caused by EV71 infection, as well as the rs4804800 polymorphism (A vs. G: OR = 1.539, 95% CI =1.229-1.928). These two DC-SIGN SNPs may have an effect on the severity of HFMD caused by EV71 infection.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. 1.

    Aswathyraj S, Arunkumar G, Alidjinou EK, Hober D (2016) Hand, foot and mouth disease (HFMD): emerging epidemiology and the need for a vaccine strategy. Med Microbiol Immunol 205:397–407

    CAS  Article  Google Scholar 

  2. 2.

    Liu SL, Pan H, Liu P, Amer S, Chan TC, Zhan J, Huo X, Liu Y, Teng Z, Wang L, Zhuang H (2015) Comparative epidemiology and virology of fatal and nonfatal cases of hand, foot and mouth disease in mainland China from 2008 to 2014. Rev Med Virol 25:115–128

    Article  Google Scholar 

  3. 3.

    Ong KC, Wong KT (2015) Understanding enterovirus 71 neuropathogenesis and its impact on other neurotropic enteroviruses. Brain Pathol 25:614–624

    CAS  Article  Google Scholar 

  4. 4.

    Chen Z, Li R, Xie Z, Huang G, Yuan Q, Zeng J (2014) IL-6, IL-10 and IL-13 are associated with pathogenesis in children with Enterovirus 71 infection. Int J Clin Exp Med 7:2718–2723

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Wang H, Lei X, Xiao X, Yang C, Lu W, Huang Z, Leng Q, Jin Q, He B, Meng G, Wang J (2015) Reciprocal regulation between enterovirus 71 and the NLRP3 inflammasome. Cell Rep 12:42–48

    CAS  Article  Google Scholar 

  6. 6.

    Shen Y, Pan Z, Zhang L, Xue W, Peng M, Hu P, Xu H, Chen M (2019) Increased effector γδ T cells with enhanced cytokine production are associated with inflammatory abnormalities in severe hand, foot, and mouth disease. Int Immunopharmacol 73:172–180

    CAS  Article  Google Scholar 

  7. 7.

    Jin Y, Zhang R, Wu W, Duan G (2018) Antiviral and inflammatory cellular signaling associated with enterovirus 71 infection. Viruses 10:155

    Article  Google Scholar 

  8. 8.

    Zhou D, Zhao Y, Kotecha A, Fry EE, Kelly JT, Wang X, Rao Z, Rowlands DJ, Ren J, Stuart DI (2019) Unexpected mode of engagement between enterovirus 71 and its receptor SCARB2. Nat Microbiol 4:414–419

    CAS  Article  Google Scholar 

  9. 9.

    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

    CAS  Article  Google Scholar 

  10. 10.

    Ren XX, Ma L, Liu QW, Li C, Huang Z, Wu L, Xiong SD, Wang JH, Wang HB (2014) The molecule of DC-SIGN captures enterovirus 71 and confers dendritic cell-mediated viral trans-infection. Virol J 11:47

    Article  Google Scholar 

  11. 11.

    Wu J, Lin K, Zeng J, Liu W, Yang F, Wang X, Xiao Y, Guo X, Nie H, Zhou T, Xu C (2014) Role of DC-SIGN in Helicobacter pylori infection of gastrointestinal cells. Front Biosci (Landmark edition) 19:825–834

    Article  Google Scholar 

  12. 12.

    Tailleux L, Pham-Thi N, Bergeron-Lafaurie A, Herrmann JL, Charles P, Schwartz O, Scheinmann P, Lagrange PH, de Blic J, Tazi A, Gicquel B, Neyrolles O (2005) DC-SIGN induction in alveolar macrophages defines privileged target host cells for mycobacteria in patients with tuberculosis. PLoS Med 2:e381

    Article  Google Scholar 

  13. 13.

    Plazolles N, Humbert JM, Vachot L, Verrier B, Hocke C, Halary F (2011) Pivotal advance: the promotion of soluble DC-SIGN release by inflammatory signals and its enhancement of cytomegalovirus-mediated cis-infection of myeloid dendritic cells. J Leukoc Biol 89:329–342

    CAS  Article  Google Scholar 

  14. 14.

    Soilleux EJ, Morris LS, Leslie G, Chehimi J, Luo Q, Levroney E, Trowsdale J, Montaner LJ, Doms RW, Weissman D, Coleman N, Lee B (2002) Constitutive and induced expression of DC-SIGN on dendritic cell and macrophage subpopulations in situ and in vitro. J Leukoc Biol 71:445–457

    CAS  PubMed  Google Scholar 

  15. 15.

    Zhang F, Ren S, Zuo Y (2014) DC-SIGN, DC-SIGNR and LSECtin: C-type lectins for infection. Int Rev Immunol 33:54–66

    CAS  Article  Google Scholar 

  16. 16.

    Liu P, Ridilla M, Patel P, Betts L, Gallichotte E, Shahidi L, Thompson NL, Jacobson K (2017) Beyond attachment: roles of DC-SIGN in dengue virus infection. Traffic (Copenhagen, Denmark) 18:218–231

    CAS  Article  Google Scholar 

  17. 17.

    Li LY, Zhang HR, Jiang ZL, Chang YZ, Shao CZ (2018) Overexpression of dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin in dendritic cells protecting against aspergillosis. Chin Med J 131:2575–2582

    Article  Google Scholar 

  18. 18.

    van der Sluis RM, van Montfort T, Pollakis G, Sanders RW, Speijer D, Berkhout B, Jeeninga RE (2013) Dendritic cell-induced activation of latent HIV-1 provirus in actively proliferating primary T lymphocytes. PLoS Pathog 9:e1003259

    Article  Google Scholar 

  19. 19.

    Tailleux L, Schwartz O, Herrmann JL, Pivert E, Jackson M, Amara A, Legres L, Dreher D, Nicod LP, Gluckman JC, Lagrange PH, Gicquel B, Neyrolles O (2003) DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells. J Exp Med 197:121–127

    CAS  Article  Google Scholar 

  20. 20.

    Ludwig IS, Lekkerkerker AN, Depla E, Bosman F, Musters RJ, Depraetere S, van Kooyk Y, Geijtenbeek TB (2004) Hepatitis C virus targets DC-SIGN and L-SIGN to escape lysosomal degradation. J Virol 78:8322–8332

    CAS  Article  Google Scholar 

  21. 21.

    Kalantari P, Bunnell SC, Stadecker MJ (2019) The C-type lectin receptor-driven, Th17 cell-mediated severe pathology in schistosomiasis: not all immune responses to helminth parasites are Th2 dominated. Front Immunol 10:26

    CAS  Article  Google Scholar 

  22. 22.

    Jiang Y, Zhang C, Chen K, Chen Z, Sun Z, Zhang Z, Ding D, Ren S, Zuo Y (2014) The clinical significance of DC-SIGN and DC-SIGNR, which are novel markers expressed in human colon cancer. PLoS ONE 9:e114748

    Article  Google Scholar 

  23. 23.

    Zhu D, Kawana-Tachikawa A, Iwamoto A, Kitamura Y (2010) Influence of polymorphism in dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin-related (DC-SIGNR) gene on HIV-1 trans-infection. Biochem Biophys Res Commun 393:598–602

    CAS  Article  Google Scholar 

  24. 24.

    Ryan EJ, Dring M, Ryan CM, McNulty C, Stevenson NJ, Lawless MW, Crowe J, Nolan N, Hegarty JE, O’Farrelly C (2010) Variant in CD209 promoter is associated with severity of liver disease in chronic hepatitis C virus infection. Hum Immunol 71:829–832

    CAS  Article  Google Scholar 

  25. 25.

    Vannberg FO, Chapman SJ, Khor CC, Tosh K, Floyd S, Jackson-Sillah D, Crampin A, Sichali L, Bah B, Gustafson P, Aaby P, McAdam KP, Bah-Sow O, Lienhardt C, Sirugo G, Fine P, Hill AV (2008) CD209 genetic polymorphism and tuberculosis disease. PLoS ONE 3:e1388

    Article  Google Scholar 

  26. 26.

    China MoHotPsRo (2010) Hand, foot and mouth disease clinical guide (2010 edition). Int J Respir 30:1473–1475

  27. 27.

    Chen X, Li S, Yang Y, Yang X, Liu Y, Liu Y, Hu W, Jin L, Wang X (2012) Genome-wide association study validation identifies novel loci for atherosclerotic cardiovascular disease. J Thromb Haemost 10:1508–1514

    CAS  Article  Google Scholar 

  28. 28.

    Lepenies B, Lee J, Sonkaria S (2013) Targeting C-type lectin receptors with multivalent carbohydrate ligands. Adv Drug Deliv Rev 65:1271–1281

    CAS  Article  Google Scholar 

  29. 29.

    Azad AK, Torrelles JB, Schlesinger LS (2008) Mutation in the DC-SIGN cytoplasmic triacidic cluster motif markedly attenuates receptor activity for phagocytosis and endocytosis of mannose-containing ligands by human myeloid cells. J Leukoc Biol 84:1594–1603

    CAS  Article  Google Scholar 

  30. 30.

    Jarvis CM, Zwick DB, Grim JC, Alam MM, Prost LR, Gardiner JC, Park S, Zimdars LL, Sherer NM, Kiessling LL (2019) Antigen structure affects cellular routing through DC-SIGN. Proc Natl Acad Sci USA 116:14862–14867

    CAS  Article  Google Scholar 

  31. 31.

    Zhang L, Xu Z, Shen DH, Zhang JF (2019) DC-SIGN molecules promote EV71 infection in dendritic cells in vitro. Chin J Clin Lab Sci 37:274–276

    Google Scholar 

  32. 32.

    Lin YW, Wang SW, Tung YY, Chen SH (2009) Enterovirus 71 infection of human dendritic cells. Exp Biol Med (Maywood) 234:1166–1173

    CAS  Article  Google Scholar 

  33. 33.

    Solomon T, Lewthwaite P, Perera D, Cardosa MJ, McMinn P, Ooi MH (2010) Virology, epidemiology, pathogenesis, and control of enterovirus 71. Lancet Infect Dis 10:778–790

    Article  Google Scholar 

  34. 34.

    Guan D, van der Sanden S, Zeng H, Li W, Zheng H, Ma C, Su J, Liu Z, Guo X, Zhang X, Liu L, Koopmans M, Ke C (2012) Population dynamics and genetic diversity of C4 strains of human enterovirus 71 in Mainland China, 1998–2010. PLoS ONE 7:e44386

    CAS  Article  Google Scholar 

Download references


The authors thank the Medical personnel of the Department of Infectious Diseases of Xi'an Jiaotong University Second Affiliated Hospital and Xi’an Children’s Hospital for their help with sample collection. The authors thank the Centre for Human Genetics Research, Shanghai Genesky Bio-Tech, for technical assistance with genotyping.


This study was funded by National Natural Science Foundation of China, Grant/Award Number 81701632 and Shaanxi Key R&D Program Project, Grant/Award Number 2017ZDXM-SF-071.

Author information




All authors discussed the results and contributed to the final manuscript. YPL and MQW performed all experiments and statistical analysis and drafted the manuscript. CRL, HLD and YW collected clinical samples. SSD and LHX conceptualized and designed the study.

Corresponding authors

Correspondence to Shuang-Suo Dang or Li-Hong Xu.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to declare.

Ethical approval and consent to participate

This study was approved by the Medical Ethics Committee of Second Affiliated Hospital of Xi'an Jiaotong University and Xi’an Children’s Hospital. Additional informed consent was obtained from all individual participants.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Handling Editor: Ana Cristina Bratanich.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Li, YP., Wang, MQ., Liu, CR. et al. Polymorphisms in the DC-SIGN gene and their association with the severity of hand, foot, and mouth disease caused by enterovirus 71. Arch Virol 166, 1133–1140 (2021). https://doi.org/10.1007/s00705-021-04991-6

Download citation