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IFN-λs inhibit Hantaan virus infection through the JAK-STAT pathway and expression of Mx2 protein

Genes & Immunity (2018) | Download Citation

Abstract

Hantaan virus (HTNV), member of the newly defined Hantaviridae family, within the order Bunyavirales, can cause a hemorrhagic fever with renal syndrome with high fatality rates in humans. However, no specific antiviral agents are currently available for HTNV infection approved by the US Food and Drug Administration. Although interferon lambdas (IFN-λs) have been shown to induce an antiviral state against HTNV, the molecular mechanisms remain to be determined. In this study, we found that IFN-λs exerted its anti-HTNV effect by activating Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway-mediated antiviral immunity in A549 cells. Simultaneously, IFN-λs downregulated suppressor of cytokine signaling proteins, which are the known negative feedback regulators of the JAK-STAT signaling pathway. Additionally, we demonstrated the role of IFN-λs-induced myxovirus resistance 2 (Mx2, also known as MxB) protein as a potential inhibitor for HTNV infection. These findings indicate that IFN-λs play an important role in cellular defenses against HTNV infection at an early stage and that human Mx2 may represent a potential therapeutic target for HTNV infection.

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Additional information

These authors contributed equally: Ning Li, Fan Luo.

References

  1. 1.

    Rissanen I, Stass R, Zeltina A, Li S, Hepojoki J, Harlos K et al. Structural transitions of the conserved and metastable hantaviral glycoprotein envelope. J Virol. 2017; 91:e00378–17.

  2. 2.

    Muyangwa M, Martynova EV, Khaiboullina SF, Morzunov SP, Rizvanov AA. Hantaviral proteins: structure, functions, and role in hantavirus infection. Front Microbiol. 2015;6:1326.

  3. 3.

    Jonsson CB, Hooper J, Mertz G. Treatment of hantavirus pulmonary syndrome. Antivir Res. 2008;78:162–9.

  4. 4.

    Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77.

  5. 5.

    Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, et al. A variant upstream of IFNL3 (IL-28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45:164–71.

  6. 6.

    Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4:63–8.

  7. 7.

    Donnelly RP, Sheikh F, Kotenko SV, Dickensheets H. The expanded family of class II cytokines that share the IL-10 receptor-2 (IL-10R2) chain. J Leukoc Biol. 2004;76:314–21.

  8. 8.

    Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R. Type III Interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol. 2007;81:7749–58.

  9. 9.

    George PM, Badiger R, Alazawi W, Foster GR, Mitchell JA. Pharmacology and therapeutic potential of interferons. Pharmacol Ther. 2012;135:44–53.

  10. 10.

    Miller DM, Klucher KM, Freeman JA, Hausman DF, Fontana D, Williams DE. Interferon lambda as a potential new therapeutic for hepatitis C. Ann NY Acad Sci. 2009;1182:80–7.

  11. 11.

    Lin FC, Young HA. Interferons: success in anti-viral immunotherapy. Cytokine Growth Factor Rev. 2014;25:369–76.

  12. 12.

    Nelson M, Rubio R, Lazzarin A, Romanova S, Luetkemeyer A, Conway B, et al. Safety and efficacy of pegylated interferon-lambda, ribavirin, and daclatasvir in HCV and HIV-coinfected patients. J Interferon Cytokine Res. 2017;37:103–11.

  13. 13.

    Galmozzi E, Vigano M, Lampertico P. Systematic review with meta-analysis: do interferon lambda 3 polymorphisms predict the outcome of interferon-therapy in hepatitis B infection? Aliment Pharmacol Ther. 2014;39:569–78.

  14. 14.

    Boisvert M, Shoukry NH. Type III interferons in hepatitis C virus infection. Front Immunol. 2016;7:628.

  15. 15.

    Yamauchi S, Takeuchi K, Chihara K, Honjoh C, Kato Y, Yoshiki H, et al. STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-lambda but not by interferon-alpha. Sci Rep. 2016;6:38336.

  16. 16.

    Griffiths SJ, Koegl M, Boutell C, Zenner HL, Crump CM, Pica F, et al. A systematic analysis of host factors reveals a Med23–interferon–lambda regulatory axis against herpes simplex virus type 1 replication. PLoS Pathog. 2013;9:e1003514.

  17. 17.

    Zhou L, Li JL, Zhou Y, Liu JB, Zhuang K, Gao JF, et al. Induction of interferon-lambda contributes to TLR3 and RIG-I activation-mediated inhibition of herpes simplex virus type 2 replication in human cervical epithelial cells. Mol Hum Reprod. 2015;21:917–29.

  18. 18.

    Hou W, Wang X, Ye L, Zhou L, Yang ZQ, Riedel E, et al. Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol. 2009;83:3834–42.

  19. 19.

    Liu MQ, Zhou DJ, Wang X, Zhou W, Ye L, Li JL, et al. IFN-lambda3 inhibits HIV infection of macrophages through the JAK-STAT pathway. PLoS ONE. 2012;7:e35902.

  20. 20.

    Chen J, Liang Y, Yi P, Xu L, Hawkins HK, Rossi SL, et al. Outcomes of congenital Zika disease depend on timing of infection and maternal–fetal interferon action. Cell Rep. 2017;21:1588–99.

  21. 21.

    Stoltz M, Ahlm C, Lundkvist A, Klingstrom J. Lambda interferon (IFN-lambda) in serum is decreased in hantavirus-infected patients, and in vitro-established infection is insensitive to treatment with all IFNs and inhibits IFN-gamma-induced nitric oxide production. J Virol. 2007;81:8685–91.

  22. 22.

    Syedbasha M, Egli A. Interferon lambda: modulating immunity in infectious diseases. Front Immunol. 2017;8:119.

  23. 23.

    Ank N, Paludan SR. Type III IFNs: new layers of complexity in innate antiviral immunity. Biofactors. 2009;35:82–87.

  24. 24.

    Odendall C, Dixit E, Stavru F, Bierne H, Franz KM, Durbin AF, et al. Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nat Immunol. 2014;15:717–26.

  25. 25.

    Krebs DL, Hilton DJ. SOCS proteins: negative regulators of cytokine signaling. Stem Cells. 2001;19:378–87.

  26. 26.

    Blumer T, Coto-Llerena M, Duong FHT, Heim MH. SOCS1 is an inducible negative regulator of interferon lambda (IFN-lambda)-induced gene expression in vivo. J Biol Chem. 2017;292:17928–38.

  27. 27.

    Wei H, Wang S, Chen Q, Chen Y, Chi X, Zhang L, et al. Suppression of interferon lambda signaling by SOCS1 results in their excessive production during influenza virus infection. PLoS Pathog. 2014;10:e1003845.

  28. 28.

    Liu B, Chen S, Guan Y, Chen L. Type III interferon induces distinct SOCS1 expression pattern that contributes to delayed but prolonged activation of Jak/STAT signaling pathway: implications for treatment non-response in HCV patients. PLoS ONE. 2015;10:e0133800.

  29. 29.

    Stoltz M, Klingstrom J. Alpha/beta interferon (IFN-/)-independent induction of IFN- 1 (interleukin-29) in response to hantaan virus infection. J Virol. 2010;84:9140–8.

  30. 30.

    Haller O, Kochs G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res. 2011;31:79–87.

  31. 31.

    Oelschlegel R, Kruger DH, Rang A. MxA-independent inhibition of Hantaan virus replication induced by type I and type II interferon in vitro. Virus Res. 2007;127:100–5.

  32. 32.

    Goujon C, Moncorge O, Bauby H, Doyle T, Ward CC, Schaller T, et al. Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature. 2013;502:559–62.

  33. 33.

    Kane M, Yadav SS, Bitzegeio J, Kutluay SB, Zang T, Wilson SJ, et al. MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature. 2013;502:563–6.

  34. 34.

    Liu Z, Pan Q, Ding S, Qian J, Xu F, Zhou J, et al. The interferon-inducible MxB protein inhibits HIV-1 infection. Cell Host Microbe. 2013;14:398–410.

  35. 35.

    Fricke T, White TE, Schulte B, de Souza Aranha Vieira DA, Dharan A, Campbell EM, et al. MxB binds to the HIV-1 core and prevents the uncoating process of HIV-1. Retrovirology. 2014;11:68.

  36. 36.

    Liu SY, Sanchez DJ, Aliyari R, Lu S, Cheng G. Systematic identification of type I and type II interferon-induced antiviral factors. Proc Natl Acad Sci USA. 2012;109:4239–44.

  37. 37.

    Durbin RK, Kotenko SV, Durbin JE. Interferon induction and function at the mucosal surface. Immunol Rev. 2013;255:25–39.

  38. 38.

    Mahlakoiv T, Hernandez P, Gronke K, Diefenbach A, Staeheli P. Leukocyte-derived IFN-alpha/beta and epithelial IFN-lambda constitute a compartmentalized mucosal defense system that restricts enteric virus infections. PLoS Pathog. 2015;11:e1004782.

  39. 39.

    Hermant P, Michiels T. Interferon-lambda in the context of viral infections: production, response and therapeutic implications. J Innate Immun. 2014;6:563–74.

  40. 40.

    Voigt EA, Yin J. Kinetic differences and synergistic antiviral effects between type I and type III interferon signaling indicate pathway independence. J Interferon Cytokine Res. 2015;35:734–47.

  41. 41.

    Kraus AA, Raftery MJ, Giese T, Ulrich R, Zawatzky R, Hippenstiel S, et al. Differential antiviral response of endothelial cells after infection with pathogenic and nonpathogenic hantaviruses. J Virol. 2004;78:6143–50.

  42. 42.

    Alff PJ, Gavrilovskaya IN, Gorbunova E, Endriss K, Chong Y, Geimonen E, et al. The pathogenic NY-1 hantavirus G1 cytoplasmic tail inhibits RIG−I− and TBK-1-directed interferon responses. J Virol. 2006;80:9676–86.

  43. 43.

    Alff PJ, Sen N, Gorbunova E, Gavrilovskaya IN, Mackow ER. The NY-1 hantavirus Gn cytoplasmic tail coprecipitates TRAF3 and inhibits cellular interferon responses by disrupting TBK1-TRAF3 complex formation. J Virol. 2008;82:9115–22.

  44. 44.

    Geimonen E, Neff S, Raymond T, Kocer SS, Gavrilovskaya IN, Mackow ER. Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses. Proc Natl Acad Sci. 2002;99:13837–42.

  45. 45.

    Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol. 2007;7:454–65.

  46. 46.

    Porritt RA, Hertzog PJ. Dynamic control of type I IFN signalling by an integrated network of negative regulators. Trends Immunol. 2015;36:150–60.

  47. 47.

    Kristiansen H, Gad HH, Eskildsen-Larsen S, Despres P, Hartmann R. The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. J Interferon Cytokine Res. 2011;31:41–7.

  48. 48.

    Pichlmair A, Lassnig C, Eberle CA, Gorna MW, Baumann CL, Burkard TR, et al. IFIT1 is an antiviral protein that recognizes 5′-triphosphate RNA. Nat Immunol. 2011;12:624–30.

  49. 49.

    Haller O, Stertz S, Kochs G. The Mx GTPase family of interferon-induced antiviral proteins. Microbes Infect. 2007;9:1636–43.

  50. 50.

    Jin HKYK, Takada A, Ogino M, Asano A, Arikawa J, Watanabe T. Mouse Mx2 protein inhibits hantavirus but not influenza virus replication. Arch Virol. 2001;146:41–9.

  51. 51.

    Aebi M, Fah J, Hurt N, Samuel CE, Thomis D, Bazzigher L, et al. cDNA structures and regulation of two interferon-induced human Mx proteins. Mol Cell Biol. 1989;9:5062–72.

  52. 52.

    Deng H-y, Luo F, Shi L-q, Zhong Q, Liu Y-j, Yang Z-q. Efficacy of arbidol on lethal hantaan virus infections in suckling mice and in vitro. Acta Pharmacol Sin. 2009;30:1015–24.

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Acknowledgements

We thank Professor Michael H. Malim (School of Medicine at Guy’s, King’s College, and St Thomas’ Hospitals) for providing the pAHM-shCtrl (CG257), pAHM-shMx2-1 (CG267), and pAHM-shMx2-2 (CG-268) vectors of silencing Mx2. The editorial services provided by Professor Wen-zhe Ho (Temple University School of Medicine) are greatly appreciated. This work was supported by research grants from the National Natural Science Foundation of China (No. 81271819) to WH and (No. 81473036) to YZ.

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    Affiliations

    1. State Key Laboratory of Virology/Institute of Medical Virology/Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan,, 430071, Hubei, China

      • Ning Li
      • , Fan Luo
      • , Qingzhou Chen
      • , Hui Wang
      • , Linlin Xie
      • , Hairong Xiong
      • , Yong Feng
      •  & Wei Hou
    2. Department of Microbiology, School of Basic Medical Sciences, Hubei University of Science and Technology, Xianning,, 437100, Hubei, China

      • Ni Zhu
      •  & Wei Hou
    3. Department of Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University, Nanjing,, 210029, Jiangsu, China

      • Ming Yue
    4. Institute of Military Medical Sciences, Nanjing Command, Nanjing,, 210002, Jiangsu, China

      • Yun Zhang

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    The authors declare that they have no conflict of interest.

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    Correspondence to Yong Feng or Wei Hou.

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    DOI

    https://doi.org/10.1038/s41435-018-0028-x