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Zika virus in the eye of the cytokine storm


Zika virus (ZIKV) is an emerging arbovirus that causes a mosquito-borne disease. Although infection with ZIKV generally leads to mild disease, its recent emergence in the Americas has been associated with an increase in the development of the Guillain-Barré syndrome in adults, as well as with neurological complications, in particular congenital microcephaly, in new-borns. Over the five past years, through the combined efforts of the scientific community, comprehensive remarkable progress aimed at deciphering the clinical, virological, physiopathological, and immunological features of ZIKV infection. This review highlights some of the most recent advances in our understanding of the role of cytokines and chemokines in ZIKV infection, and discusses potential links to pathogenesis.

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  1. 1.

    Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological specificity. Trans R Soc Tropl Med Hyg 1952; 46: 509–20.

  2. 2.

    Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap island, federated states of Micronesia. N Engl J Med 2009; 360: 2536–43.

  3. 3.

    Musso D, Bossin H, Mallet HP, et al. Zika virus in French Polynesia 2013-14: anatomy of a completed outbreak. Lancet Infect Dis 2018; 18: el72–82.

  4. 4.

    Zhang Q, Sun K, Chinazzi M, et al. Spread of Zika virus in the Americas. Proc Natl Acad Sci USA 2017; 114: E4334–43.

  5. 5.

    WHO. WHO statement on the first meeting of the International Health Regulations (2005) (IHR 2005) Emergency Committee on Zika virus and observed increase in neurological disorders and neonatal malformations. 2016. http://www.who.int/mediacentre/news/statements/2016/lst-emergency-committee-zika/en/ (accessed March 16, 2016).

  6. 6.

    Gould EA, Solomon T. Pathogenic flaviviruses. Lancet 2008; 71: 500–9.

  7. 7.

    Cao-Lormeau VM, Blake A, Mons S, et al. Guillain-Barr. Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study. Lancet 2016; 387: 1531–9.

  8. 8.

    Carteaux G, Maquart M, Bedet A, et al. Zika virus associated with meningoencephalitis. N Engl J Med 2016; 374: 1595–6.

  9. 9.

    Mecharles S, Herrmann C, Poullain P, et al. Acute myelitis due to Zika virus infection. Lancet 2016; 387: 1481.

  10. 10.

    Campos GS, Bandeira AC, Sardi SI. Zika virus outbreak, Bahia, Brazil. Emerg Infect Dis 2015; 21: 1885–6.

  11. 11.

    Ventura CV, Maia M, Bravo-Filho V, Góis AL, Beifort Jr R. Zika virus in Brazil and macular atrophy in a child with microcephaly. Lancet 2016; 387: 228.

  12. 12.

    Mlakar J, Korva M, Tul N, et al. Zika virus associated with microcephaly. N Engl J Med 2016; 374: 951–8.

  13. 13.

    D’Ortenzio E, Matheron S, Yazdanpanah Y, et al. Evidence of sexual transmission of Zika virus. N Engl J Med 2016; 374: 2195–8.

  14. 14.

    Barzon L, Pacenti M, Franchin E, et al. Infection dynamics in a traveller with persistent shedding of Zika virus RNA in semen for six months after returning from Haiti to Italy, January 2016. Eurosurveillance 2016; 21: 30316.

  15. 15.

    Murray KO, Gorchakov R, Carlson AR, et al. Prolonged detection of Zika virus in vaginal secretions and whole blood. Emerg Infect Dis 2017; 23: 99–101.

  16. 16.

    Liu ZY, Shi WF, Qin CF. The evolution of Zika virus from Asia to the Americas. Nat Rev Microbiol 2019; 17: 131–9.

  17. 17.

    Lambrechts L, Scott TW, Gubler DJ. Consequences of the expanding global distribution of Aedes albopictus for dengue virus transmission. PLoS Negl Trop Dis 2010; 4: e646.

  18. 18.

    Petitdemange C, Wauquier N, Vieillard V. Control of immunopathology during Chikungunya virus infection. J Allergy Clin Immunol 2015; 135: 846–55.

  19. 19.

    Hamel R, Dejarnac O, Wichit S, et al. Biology of Zika virus infection in human skin cells. J Virol 2015; 89: 8880–96.

  20. 20.

    Nowakowski TJ, Pollen AA, Di Lullo E, Sandoval-Espinosa C, Bershteyn M, Kriegstein AR. Expression analysis highlights AXL as a candidate Zika virus entry receptor in neural stem cells. Cell Stem Cell 2016; 18: 591–6.

  21. 21.

    Ngono AE, Shresta S. Immune response to Dengue and Zika. Annu Rev Immunol 2018; 36: 279–308.

  22. 22.

    Meylan E, Tschopp J, Karin M. Intracellular pattern recognition receptors in the host response. Nature 2006; 442: 39–44.

  23. 23.

    Sadler AJ, Williams BRG. Interferon-inducible antiviral effectors. Nat Rev Immunol 2008; 8: 559–68.

  24. 24.

    Honda K, Taniguchi T. IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 2006; 6: 644–58.

  25. 25.

    Schoggins J, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol 2011; 1: 519–25.

  26. 26.

    Versteeg GA, Garcia-Sastre A. Viral tricks to grid-lock the type I interferon system. Curr Opin Microbiol 2010; 13: 508–16.

  27. 27.

    Lubick KJ, Robertson SJ, McNally KL, et al. Flavivirus antagonism of type I interferon signaling reveals prolidase as a regulator of IFNAR1 surface expression. Cell Host Microbe 2015; 18: 61–74.

  28. 28.

    Laurent-Rolle M, Morrison J, Rajsbaum R, et al. The interferon signaling antagonist function of yellow fever virus NS5 protein is activated by type I interferon. Cell Host Microbe 2014; 16: 314–27.

  29. 29.

    Morrison J, Laurent-Rolle M, Maestre AM, et al. Dengue virus co-opts UBR4 to degrade STAT2 and antagonize type I interferon signaling. PLoS Pathog 2013; 9: el003265.

  30. 30.

    Grant A, Ponia SS, Tripathi S, et al. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 2016; 19: 882–90.

  31. 31.

    Sheridan MA, Yunusov D, Balaraman V, Alexenko AP, Yabe S, Verjovski-Almeida S. Vulnerability of primitive human placental trophoblast to Zika virus. Proc Natl Acad Sci USA 2017; 114: E1587–96.

  32. 32.

    Jewell NA, Cline T, Mertz SE, et al. Lambda interferon is the predominant interferon induced by influenza A virus infection in vivo. J Virol 2010; 84: 11515–22.

  33. 33.

    Tarín JJ, Gómez-Piquer V. Do women have a hidden heat period? Hum Reprod 2002; 17: 2243–8.

  34. 34.

    Bayer A, Lennemann NJ, Ouyang Y, et al. Type III interferons produced by human placental trophoblasts confer protection against Zika virus infection. Cell Host Microbe 2016; 19: 705–12.

  35. 35.

    Caine EA, Scheaffer SM, Arora N, et al. Interferon lambda protects the female reproductive tract against Zika virus infection. Nat Commun 2019; 10: 280.

  36. 36.

    Lum FM, Lye DCB, Tan JJL, et al. Longitudinal study of cellular and systemic cytokine signatures to define the dynamics of a balanced immune environment during disease manifestation in Zika virus-infected patients. J Infect Dis 2018; 218: 814–24.

  37. 37.

    Tappe D, Pérez-Girón JV, Zammarchi L, et al. Cytokine kinetics of Zika virus-infected patients from acute to reconvalescent phase. Med Microbiol Immunol 2016; 205: 269–73.

  38. 38.

    Barros JBS, da Silva PAN, Koga RCR, et al. Acute Zika virus infection in an endemic area shows modest proinflammatory systemic immunoactivation and cytokine-symptom associations. Front Immunol 2018; 9: 821.

  39. 39.

    Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 2014; 32: 513–45.

  40. 40.

    Gasser S, Raulet DH. Activation and self-tolerance of natural killer cells. Immunol Rev 2006; 214: 130–42.

  41. 41.

    Sun JC, Lanier LL. NK cell development, homeostasis and function: parallels with CD8+ Tcells. Nat Rev Immunol 2011; 11: 645–57.

  42. 42.

    Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science 2011; 331: 44–9.

  43. 43.

    Glasner A, Oiknine-Djian E, Weisblum Y, et al. Zika virus escapes NK cell detection by upregulating major histocompatibility complex class I molecules. J Virol 2017; 91: e00785–817.

  44. 44.

    Lum FM, Lee D, Chua TK, et al. Zika virus infection preferentially counterbalances human peripheral monocyte and/or NK cell activity. mSphere 2018; 3: e00120–218.

  45. 45.

    Maucourant C, Petitdemange C, Yssel H, Vieillard V. Control of acute arboviral infection by natural killer cells. Viruses 2019; 11: E131.

  46. 46.

    Petitdemange C, Wauquier N, Devilliers H, et al. Longitudinal analysis of natural killer cells in Dengue virus-infected patients in comparison to Chikungunya and Chikungunya/Dengue virus-infected patients. PLoS Negl Trop Dis 2016; 10: e0004499.

  47. 47.

    Petitdemange C, Becquart P, Wauquier N, et al. Unconventional repertoire profile is imprinted during acute Chikungunya infection for natural killer cells polarization toward cytotoxicity. PLoS Pathog 2011; 7: el002268.

  48. 48.

    Malmberg KJ, Beziat V, Ljunggren HG. Spotlight on NKG2C and the human NK-cell response to CMV infection. Eur J Immunol 2012; 42: 3141–5.

  49. 49.

    Zhang M, Daniel S, Huang Y, et al. Anti-West Nile virus activity of in vitro expanded human primary natural killer cells. BMC Immunol 2010; 11: 3.

  50. 50.

    Chaudhary V, Yuen KS, Chan JF, et al. Selective activation of type ii interferon signaling by Zika virus NS5 protein. J Virol 2017; 91: e00163–217.

  51. 51.

    Pandey N, Jain A, Garg RK, et al. Serum levels of IL-8, IFNγ, IL-10 and TGF ß and their gene expression levels in severe and non-severe cases of dengue virus infection. Arch Virol 2015; 160: 1463–75.

  52. 52.

    Her Z, Kam YW, Gan VC, et al. Severity of plasma leakage is associated with high levels of interferon γ-inducible protein 10, hepatocyte growth factor, matrix metalloproteinase 2 (MMP-2) and MMP-9 during Dengue virus infection. J Infect Dis 2017; 215: 42–51.

  53. 53.

    Zhao L, Huang X, Hong W, et al. Slow resolution of inflammation in severe adult dengue patients. BMC Infect Dis 2016; 16: 291.

  54. 54.

    Dejnirattisai W, Supasa P, Wongwiwat W, et al. Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with zika virus. Nat Immunol 2016; 17: 1102–8.

  55. 55.

    Halstead SB. Pathogenic exploitation of Fc activity. In: Ackerman M, ed. Antibody Fc linking adaptive and innate immunity. Cambridge, MA: Academic Press.

  56. 56.

    Martin-Acebes MA, Saiz JC, Jiménez de Oya N. Antibody-dependent enhancement and Zika: real threat or phantom menace? Front Cell Infect Microbiol 2018; 8: 44.

  57. 57.

    Khandia R, Munjal A, Dhama K, et al. Modulation of Dengue/ Zika virus pathogenicity by antibody-dependent enhancement and strategies to protect against enhancement in Zika virus infection. Front Immunol 2018; 9: 597.

  58. 58.

    WHO. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barré syndrome. http://www.who.int/mediacentre/news/statements/2016/emergency-committee-zika-microcephaly/en/# (accessed February 1, 2016).

  59. 59.

    Racicot K, Kwon JY, Aldo P, Silasi M, Mor G. Understanding the complexity of the immune system during pregnancy. Am J Reprod Immunol 2014; 72: 107–16.

  60. 60.

    Heymann DL, Hodgson A, Sall AA, et al. Zika virus and microcephaly: why is this situation a PHEIC? Lancet 2016; 387: 719–21.

  61. 61.

    de Araújo TVB, Ximenes RAA, Miranda-Filho DB, et al. Investigators from the Microcephaly Epidemic Research Group; Brazilian Ministry of Health; Pan American Health Organization; Instituto de Medicina Integral Professor Fernando Figueira; State Health Department of Pernambuco. Association between microcephaly, Zika virus infection and other risk factors in Brazil: final report of a case-control study. Lancet Infect Dis 2018; 18: 328–36.

  62. 62.

    Ashwal S, Michelson D, Plawner L, Dobyns WB, Quality Standards Subcommittee of the American Academy of Neurology, the Practice Committee of the Child Neurology Society. Practice parameter: evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2009; 73: 887–97.

  63. 63.

    Calvet G, Aguiar RS, Melo ASO, et al. Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis 2016; 16: 653–60.

  64. 64.

    van den Pol AN, Mao G, Yang Y, Ornaghi S, Davis JN. Zika virus targeting in the developing brain. J Neurosci 2017; 37: 2161–75.

  65. 65.

    Diop F, Vial T, Ferraris P, et al. Zika virus infection modulates the metabolomic profile of microglial cells. PLoS One 2018; 13: e0206093.

  66. 66.

    Naveca FG, Pontes GS, Chang AY, et al. Analysis of the immunological biomarker profile during acute Zika virus infection reveals the overexpression of CXCL10, a chemokine linked to neuronal damage. Mem Inst Oswaldo Cruz 2018; 113: el70542.

  67. 67.

    Foo SS, Chen W, Chan Y, et al. Biomarkers and immunoprofiles associated with fetal abnormalities of ZIKV-positive pregnancies. ICI Insight 2018; 3: 21.

  68. 68.

    Shi C, Pamer EG. Monocyte recruitment during infection and inflammation. Nat Rev Immunol 2011; 11: 762–74.

  69. 69.

    Wang Y, Zhang J, Luo P, Zhu J, Feng J, Zhang HL. Tumor necrosis factor-alpha in Guillain-Barré syndrome, friend or foe? Expert Opin Ther Targets 2017; 21: 103–12.

  70. 70.

    Faas MM, Spaans F, De Vos P. Monocytes and macrophages in pregnancy and pre-eclampsia. Front Immunol 2014; 5: 298.

  71. 71.

    Gervasi MT, Chaiworapongsa T, Naccasha N, et al. Phenotypic and metabolic characteristics of maternal monocytes and granulocytes in preterm labor with intact membranes. Am J Obstet Gynecol 2001; 185: 1124–9.

  72. 72.

    Faas MM, de Vos P. Uterine NK cells and macrophages in pregnancy. Placenta 2017; 56: 44–52.

  73. 73.

    Saito S, Nishikawa K, Morii T, Enomoto M, Narita N, Motoyoshi K, Ichijo M. Cytokine production by CD16-CD56bright natural killer cells in the human early pregnancy decidua. Int Immunol 1993; 5: 559–63.

  74. 74.

    Foo SS, Chen W, Chan Y, et al. Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2017; 2: 1558–70.

  75. 75.

    Brooks DG, Trifilo MJ, Edelmann KH, Teyton L, McGavern DB, Oldstone MB. Interleukin-10 determines viral clearance or persistence in vivo. Nat Med 2006; 12: 1301–9.

  76. 76.

    Ornelas AM, Pezzuto P, Silveira PP, et al. Immune activation in amniotic fluid from Zika virus-associated microcephaly. Ann Neurol 2017; 81: 152–6.

  77. 77.

    Willison HJ, Jacobs BC, van Doom PA. Guillain-Barré syndrome. Lancet 2016; 388: 717–27.

  78. 78.

    Ioos S, Mallet HP, Leparc Goffart I, Gauthier V, Cardoso T, Herida M. Current Zika virus epidemiology and recent epidemics. Med Mal Infect 2014; 44: 302–7.

  79. 79.

    WHO. WHO Emergencies preparedness, response. Guillain-Barré syndrome-Brazil. 2016. http://www.who.int/csr/don/8-february-2016-gbs-brazil/en/ (accessed 19 February 2016).

  80. 80.

    Nyati KK, Prasad KN. Role of cytokines and Toll-like receptors in the immunopathogenesis of Guillain-Barré syndrome. Mediators Inflamm 2014; 2014: 758639.

  81. 81.

    Peng J, Zhang H, Liu P, et al. IL-23 and IL-27 levels in serum are associated with the process and the recovery of Guillain-Barré syndrome. Sci Rep 2018; 8: 2824.

  82. 82.

    Chiang S, Ubogu EE. The role of chemokines in Guillain-Barré syndrome. Muscle Nerve 2013; 48: 320–30.

  83. 83.

    Barrett ADT. Current status of Zika vaccine development: Zika vaccines advance into clinical evaluation. NPJ Vaccines 2018; 3: 24.

  84. 84.

    Diamond MS, Ledgerwood JE, Pierson TC. Zika virus vaccine development: Progress in the face of new challenges. Annu Rev Med 2019; 70: 121–35.

  85. 85.

    Nie CQ, Bernard NJ, Norman MU, et al. IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection. PLoS Pathog 2009; 5: el000369.

  86. 86.

    Grip O, Janciauskiene S. Atorvastatin reduces plasma levels of chemokine (CXCL10) in patients with Crohn’s disease. PLoS One 2009; 4: e5263.

  87. 87.

    Liu M, Guo S, Hibbert JM, et al. CXCLl0/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev 2011; 22: 121–30.

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This study was supported by the EU Horizon 2020 ZIKAlliance Program (grant agreement no. 734548).

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Correspondence to Vincent Vieillard.

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Disclosure.Financial support: none. Conflict of interest: none.

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Maucourant, C., Queiroz, G.A.N., Samri, A. et al. Zika virus in the eye of the cytokine storm. Eur Cytokine Netw 30, 74–81 (2019). https://doi.org/10.1684/ecn.2019.0433

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Key words

  • Zika virus
  • Flavivirus
  • Cytokines
  • Chemokines
  • Microcephaly
  • Guillain-Barré syndrome