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Virologica Sinica

, Volume 33, Issue 6, pp 545–556 | Cite as

The Scorpion Venom Peptide Smp76 Inhibits Viral Infection by Regulating Type-I Interferon Response

  • Zhenglin Ji
  • Fangfang Li
  • Zhiqiang Xia
  • Xingchen Guo
  • Minjun Gao
  • Fang Sun
  • Yuting Cheng
  • Yingliang Wu
  • Wenxin Li
  • Syed Abid Ali
  • Zhijian CaoEmail author
Research Article

Abstract

Dengue virus (DENV) and Zika virus (ZIKV) have spread throughout many countries in the developing world and infect millions of people every year, causing severe harm to human health and the economy. Unfortunately, there are few effective vaccines and therapies available against these viruses. Therefore, the discovery of new antiviral agents is critical. Herein, a scorpion venom peptide (Smp76) characterized from Scorpio maurus palmatus was successfully expressed and purified in Escherichia coli BL21(DE3). The recombinant Smp76 (rSmp76) was found to effectively inhibit DENV and ZIKV infections in a dose-dependent manner in both cultured cell lines and primary mouse macrophages. Interestingly, rSmp76 did not inactivate the viral particles directly but suppressed the established viral infection, similar to the effect of interferon (IFN)-β. Mechanistically, rSmp76 was revealed to upregulate the expression of IFN-β by activating interferon regulatory transcription factor 3 (IRF3) phosphorylation, enhancing the type-I IFN response and inhibiting viral infection. This mechanism is significantly different from traditional virucidal antimicrobial peptides (AMPs). Overall, the scorpion venom peptide Smp76 is a potential new antiviral agent with a unique mechanism involving type-I IFN responses, demonstrating that natural AMPs can enhance immunity by functioning as immunomodulators.

Keywords

Dengue virus (DENV) Zika virus (ZIKV) Scorpion venom peptide Smp76 Antiviral mechanism Type-I interferon response 

Notes

Acknowledgements

We are indebted to Dr. Bo Zhang from the Wuhan Institute of Virology, Chinese Academy of Sciences for kindly providing DENV serotype-2 TSV01 strain. We thank Dr. Ren Sun and Dr. Danyang Gong from the University of California, Los Angeles for sharing pBR322-Z2 plasmid. We gratefully acknowledge Prof. Wu Jianguo and Prof. Bo Zhong from Wuhan University for their kindly providing DENV-2 (NGC) and Ifnar1-/- mice, respectively. This work was supported by grants from National Science Fund of China (Nos. 31572289, 31872239 and 81630091), International S&T Cooperation Program of China (No. S2016G3110), Hubei Science Fund (Nos. 2015CFA042 and 2016CFA018), China-Kazakhstan Cooperation Program (No. CK-07-09), and Fundamental Research Funds for the Central Universities in China (Nos. 2042017kf0242 and 2042017kf0199). SAA is grateful for financial support from Higher Education Commission (HEC) of Pakistan.

Author Contributions

FFL, ZQX, XCG and ZLJ designed the experiments and analyzed the data. ZLJ, FS and MJG performed most of the experiments. ZLJ and YTC wrote the manuscript. SAA, WXL, YLW and ZJC revised the manuscript. All authors read and approved the final manuscript.

Compliance with Ethics Standards

Conflict of interest

The authors declare that they have no competing interests.

Animal and Human Rights Statement

All animal experiments were in accordance with and were approved by the Institutional Animal Care and Use Committee of Wuhan University (Wuhan, China).

Supplementary material

12250_2018_68_MOESM1_ESM.pdf (403 kb)
Supplementary material 1 (PDF 403 kb)

References

  1. Abdel-Rahman MA, Quintero-Hernandez V, Possani LD (2013) Venom proteomic and venomous glands transcriptomic analysis of the Egyptian scorpion Scorpio maurus palmatus (Arachnida: Scorpionidae). Toxicon 74:193–207CrossRefGoogle Scholar
  2. Alesha Grant SS, Tripathi Shashank, Balasubramaniam Vinod, Lisa Miorin MS, Schwarz Megan C, Sánchez-Seco Mari Paz, Matthew J, Evans SM, García-Sastre A (2016) Zika virus impairs growth in human neurospheres and brain organoids. Cell Host Microbe 19:882–890CrossRefGoogle Scholar
  3. Biragyn A, Ruffini PA, Leifer CA, Klyushnenkova E, Shakhov A, Chertov O, Shirakawa AK, Farber JM, Segal DM, Oppenheim JJ, Kwak LW (2002) Toll-like receptor 4-dependent activation of dendritic cells by β-Denfensin 2. Science 298:1025–1029CrossRefGoogle Scholar
  4. Bogoch II, Brady OJ, Kraemer MU, German M, Creatore MI, Brent S, Watts AG, Hay SI, Kulkarni MA, Brownstein JS, Khan K (2016) Potential for Zika virus introduction and transmission in resource-limited countries in Africa and the Asia-Pacific region: a modelling study. Lancet Infect Dis 16:1237–1245CrossRefGoogle Scholar
  5. Carballar-Lejarazu R, Rodriguez MH, Hernandez-Hernandez FC, Ramos-Castaneda J, Possani LD, Zurita-Ortega M, Reynaud-Garza E, Hernandez-Rivas R, Loukeris T, Lycett G, Lanz-Mendoza H (2008) Recombinant scorpine: a multifunctional antimicrobial peptide with activity against different pathogens. Cell Mol Life Sci 65:3081–3092CrossRefGoogle Scholar
  6. Chan JF, Choi GK (2016) Zika fever and congenital Zika syndrome: an unexpected emerging arboviral disease. J Infect Dis 220:449Google Scholar
  7. Cui X, Wu Y, Fan D, Gao N, Ming Y, Wang P, An J (2018) Peptides P4 and P7 derived from E protein inhibit entry of dengue virus serotype 2 via interacting with β3 integrin. Antivir Res 155:20–27CrossRefGoogle Scholar
  8. Dai JF, Pan W, Wang PH (2011) ISG15 facilitates cellular antiviral response to dengue and west nile virus infection in vitro. Virol J 8:486–492CrossRefGoogle Scholar
  9. Easton DM, Nijnik A, Mayer ML, Hancock RE (2009) Potential of immunomodulatory host defense peptides as novel anti-infectives. Trends Biotechnol 27:582–590CrossRefGoogle Scholar
  10. Halstead SB (2007) Dengue. Lancet 370:1644–1652CrossRefGoogle Scholar
  11. Hancock RE, Finlay BB (2004) Can innate immunity be enhanced to treat microbial infections. Nat Rev Microbiol 2:497–504CrossRefGoogle Scholar
  12. Heymann DL, Hodgson A, Sall AA, Freedman DO, Staples JE, Althabe F, Baruah K, Mahmud G, Kandun N, Vasconcelos FC, Bino S, Menon KU (2016) Zika virus and microcephaly: why is this situation a PHEIC? Lancet 387:719–721CrossRefGoogle Scholar
  13. Hilchie AL, Wuerth K, Hancock RE (2013) Immune modulation by multifaceted cationic host defense (antimicrobial) peptides. Nat Chem Biol 9:761–768CrossRefGoogle Scholar
  14. Hishiki T, Han QE, Arimoto K, Shimotohno K, Igarashi T, Vasudevan SG, Suzuki Y, Yamamoto N (2014) Interferon-mediated ISG15 conjugation restricts dengue virus 2 replication. Biochem Biophys Res Commun 448:95–100CrossRefGoogle Scholar
  15. Holthausen DJ, Lee SH, Kumar VT, Bouvier NM, Krammer F, Ellebedy AH, Wrammert J, Lowen AC, George S, Pillai MR, Jacob J (2017) An amphibian host defense peptide is virucidal for human H1 hemagglutinin-bearing influenza viruses. Immunity 46:587–595CrossRefGoogle Scholar
  16. Hong W, Zhang R, Di Z, He Y, Zhao Z, Hu J, Wu Y, Li W, Cao Z (2013) Design of histidine-rich peptides with enhanced bioavailability and inhibitory activity against hepatitis C virus. Biomaterials 34:3511–3522CrossRefGoogle Scholar
  17. Hong W, Li T, Song Y, Zhang R, Zeng Z, Han S, Zhang X, Wu Y, Li W, Cao Z (2014) Inhibitory activity and mechanism of two scorpion venom peptides against herpes simplex virus type 1. Antivir Res 102:1–10CrossRefGoogle Scholar
  18. Jiang SB, Lin K, Strick N, Neurath AR (1993) HIV-1 inhibition by a peptide. Nature 365:113CrossRefGoogle Scholar
  19. Jones M, Davidson A, Hibbert L, Gruenwald P, Schlaak J, Ball S, Foster GR, Jacobs M (2005) Dengue virus inhibits alpha interferon signaling by reducing STAT2 expression. J Virol 79:5414–5420CrossRefGoogle Scholar
  20. Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, Cao W, Wang YH, Su B, Nestle FO, Zal T, Mellman I, Schroder JM, Liu YJ, Gilliet M (2007) Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449:564–569CrossRefGoogle Scholar
  21. Lin RJ, Yu HP, Chang BL, Tang WC, Liao CL, Lin YL (2009) Distinct antiviral roles for human 2′,5′-oligoadenylate synthetase family members against dengue virus infection. J Immunol 183:8035–8043CrossRefGoogle Scholar
  22. Loo YM, Gale M Jr (2011) Immune signaling by RIG-I-like receptors. Immunity 34:680–692CrossRefGoogle Scholar
  23. McMichael AJ, Woodruff RE, Hales S (2006) Climate change and human health: present and future risks. Lancet 367:859–869CrossRefGoogle Scholar
  24. Morrison J, Laurent-Rolle M, Maestre AM, Rajsbaum R, Pisanelli G, Simon V, Mulder LC, Fernandez-Sesma A, Garcia-Sastre A (2013) Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. PLoS Pathog 9:e1003265CrossRefGoogle Scholar
  25. Muller U, Steinhoff U, Reis LF, Hemmi S, Paviovic J, Zinkernagel RM, Aguet M (1994) Functional role of type I and type II Interferons in antiviral defense. Science 264:1918–1921CrossRefGoogle Scholar
  26. Pichlmair A, Reis e Sousa C (2007) Innate recognition of viruses. Immunity 27:370–383CrossRefGoogle Scholar
  27. Reddy KV, Yedery RD, Aranha C (2004) Antimicrobial peptides: premises and promises international. J Antimicrob Agents 24:536–547CrossRefGoogle Scholar
  28. Renaud Conde FZ, Rodriguez Mario H, Possani Lourival D (2000) Scorpine, an anti-malaria and anti-bacterial agent purified from scorpion venom. FEBS Lett 471:165–168CrossRefGoogle Scholar
  29. Sainz B, Halford WP (2002) Alpha/beta interferon and gamma interferon synergize to inhibit the replication of herpes simplex virus type 1. J Virol 76:11541–11550CrossRefGoogle Scholar
  30. Schmidt AG, Yang PL, Harrison SC (2010) Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate. PLoS Pathog 6:e1000851CrossRefGoogle Scholar
  31. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, Rice CM (2011) A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481–485CrossRefGoogle Scholar
  32. Scott MG, Dullaghan E, Mookherjee N, Glavas N, Waldbrook M, Thompson A, Wang A, Lee K, Doria S, Hamill P, Yu JJ, Li Y, Donini O, Guarna MM, Finlay BB, North JR, Hancock RE (2007) An anti-infective peptide that selectively modulates the innate immune response. Nat Biotechnol 25:465–472CrossRefGoogle Scholar
  33. Screaton G, Mongkolsapaya J, Yacoub S, Roberts C (2015) New insights into the immunopathology and control of dengue virus infection. Nat Rev Immunol 15:745–759CrossRefGoogle Scholar
  34. Seth RB, Sun L, Chen ZJ (2006) Antiviral innate immunity pathways. Cell Res 16:141–147CrossRefGoogle Scholar
  35. Shepard DS, Undurraga EA, Halasa YA, Stanaway JD (2016) The global economic burden of dengue: a systematic analysis. Lancet Infect Dis 16:935–941CrossRefGoogle Scholar
  36. Theofilopoulos AN, Baccala R, Beutler B, Kono DH (2005) Type I interferons (alpha/beta) in immunity and autoimmunity. Annu Rev Immunol 23:307–336CrossRefGoogle Scholar
  37. Uawonggul N, Sukprasert S, Incamnoi P, Patramanon R, Thammasirirak S, Preecharram S, Bunyatratchata W, Kuaprasert B, Daduang J, Daduang S (2014) Bacterial overexpression ofrecombinant heteroscorpine-1 (rHS-1), a toxin from Heterometrus laoticus scorpion venom: trends forantibacterial application and antivenom production. Biochem Genet 52:459–473CrossRefGoogle Scholar
  38. Ubol S, Masrinoul P, Chaijaruwanich J, Kalayanarooj S, Charoensirisuthikul T, Kasisith J (2008) Differences in global gene expression in peripheral blood mononuclear cells indicate a significant role of the innate responses in progression of dengue fever but not dengue hemorrhagic fever. J Infect Dis 197:1459–1467CrossRefGoogle Scholar
  39. Yasin B, Wang W, Pang M, Cheshenko N, Hong T, Waring AJ, Herold BC, Wagar EA, Lehrer RI (2004) θ Defensins protect cells from infection by herpes simplex virus by inhibiting viral adhesion and entry. J Virol 78:5147–5156CrossRefGoogle Scholar
  40. Yu JS, Tseng CK, Lin CK, Hsu YC, Wu YH, Hsieh CL, Lee JC (2017a) Celastrol inhibits dengue virus replication via up-regulating type I interferon and downstream interferon-stimulated responses. Antivir Res 137:49–57CrossRefGoogle Scholar
  41. Yu Y, Deng Y, Zou P, Wang Q, Dai Y, Yu F, Du L, Zhang N, Tian M, Hao J, Meng Y, Li Y, Zhou X, Chan JF, Yuen KY, Qin CF, Jiang SB, Lu L (2017b) A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nat Commun 8:15672CrossRefGoogle Scholar
  42. Zeng Z, Zhang R, Hong W, Cheng Y, Wang H, Lang Y, Ji Z, Wu Y, Li W, Xie Y, Cao Z (2018) Histidine-rich modification of a scorpion-derived peptide improves bioavailability and inhibitory activity against HSV-1. Theranostics 8:199–211CrossRefGoogle Scholar
  43. Zhao Z, Hong W, Zeng Z, Wu Y, Hu K, Tian X, Li W, Cao Z (2012) Mucroporin-M1 inhibits hepatitis B virus replication by activating the mitogen-activated protein kinase (MAPK) pathway and down-regulating HNF4alpha in vitro and in vivo. J Biol Chem 287:30181–30190CrossRefGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.State Key Laboratory of Virology, Modern Virology Research Center, College of Life SciencesWuhan UniversityWuhanChina
  2. 2.Bio-drug Research CenterWuhan UniversityWuhanChina
  3. 3.International Centre for Chemical and Biological Sciences (ICCBS), HEJ Research Institute of ChemistryUniversity of KarachiKarachiPakistan
  4. 4.Hubei Province Engineering and Technology Research, Center for Fluorinated PharmaceuticalsWuhan UniversityWuhanChina

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