Innate immune response in patients with acute Zika virus infection

  • Marcelo Henrique Matias da Silva
  • Raiza Nara Cunha Moises
  • Brenda Elen Bizerra Alves
  • Hannaly Wana Bezerra Pereira
  • Anne Aline Pereira de Paiva
  • Ingryd Câmara Morais
  • Yasmim Mesquita Nascimento
  • Joelma Dantas Monteiro
  • Janeusa Trindade de Souto
  • Manuela Sales Lima Nascimento
  • Josélio Maria Galvão de Araújo
  • Paulo Marcos Matta da GuedesEmail author
  • José Veríssimo FernandesEmail author
Original Investigation


Innate immunity receptors (Toll-like receptors/TLRs and RIG-like receptors/RLRs) are important for the initial recognition of Zika virus (ZIKV), modulation of protective immune response, and IFN-α and IFN-β production. Immunological mechanisms involved in protection or pathology during ZIKV infection have not yet been determined. In this study, we evaluated the mRNA expression of innate immune receptors (TLR3, TLR7, TLR8, TLR9, melanoma differentiation-associated protein 5/MDA-5, and retinoic acid inducible gene/RIG-1), its adapter molecules (Myeloid Differentiation Primary Response Gene 88/Myd88, Toll/IL-1 Receptor Domain-Containing Adaptor-Inducing IFN-β/TRIF), and cytokines (IL-6, IL-12, TNF-α, IFN-α, IFN-β, and IFN-γ) in the acute phase of patients infected by ZIKV using real-time PCR in peripheral blood. Patients with acute ZIKV infection had high expression of TLR3, IFN-α, IFN-β, and IFN-γ when compared to healthy controls. In addition, there was a positive correlation between TLR3 expression compared to IFN-α and IFN-β. Moreover, viral load is positively correlated with TLR8, RIG-1, MDA-5, IFN-α, and IFN-β. On the other hand, patients infected by ZIKV showed reduced expression of RIG-1, TLR8, Myd88, and TNF-α molecules, which are also involved in antiviral immunity. Similar expressions of TLR7, TLR9, MDA-5, TRIF, IL-6, and IL-12 were observed between the group of patients infected with ZIKV and control subjects. Our results indicate that acute infection (up to 5 days after the onset of symptoms) by ZIKV in patients induces the high mRNA expression of TLR3 correlated to high expression of IFN-γ, IFN-α, and IFN-β, even though the high viral load is correlated to high expression of TLR8, RIG-1, MDA-5, IFN-α, and IFN-β in ZIKV patients.


Zika virus Patient Innate immune receptors Toll-like receptors (TLRs) RIG-like receptors (RLRs) Cytokines 



This work was supported by the National Council for Scientific and Technological Development (MEC/MCTI/CAPES/CNPq/FAPS-PVE Grant no. 400328/2014-3 and MCTI/CNPq/Universal Grant no. 404904/2016-5). Post-graduation research fellows are supported by University Faculty Advanced Studies Coordination Unit (CAPES). The author PMMG acknowledges the CNPq for the research productivity fellowship.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to declare.


  1. 1.
    Hayes EB (2009) Zika virus outside Africa. Emerg Infect Dis 15:1347–1350. CrossRefGoogle Scholar
  2. 2.
    Kucharski AJ, Funk S, Eggo RM et al (2016) Transmission dynamics of Zika virus in island populations: a modelling analysis of the 2013–14 French Polynesia outbreak. PLoS Negl Trop Dis 10:1–15. CrossRefGoogle Scholar
  3. 3.
    Tognarelli J, Ulloa S, Villagra E et al (2016) A report on the outbreak of Zika virus on Easter Island, South Pacific, 2014. Arch Virol 161:665–668. CrossRefGoogle Scholar
  4. 4.
    Zanluca C, De Melo VCA, Mosimann ALP et al (2015) First report of autochthonous transmission of Zika virus in Brazil. Mem Inst Oswaldo Cruz 110:569–572. CrossRefGoogle Scholar
  5. 5.
    Calvet G, Aguiar RS, Melo ASO et al (2016) Detection and sequencing of Zika virus from amniotic fluid of fetuses with microcephaly in Brazil: a case study. Lancet Infect Dis 16:653–660. CrossRefGoogle Scholar
  6. 6.
    Ikejezie J, Shapiro CN, Kim J et al (2017) Zika virus transmission—region of the Americas, May 15, 2015–December 15, 2016. Am J Transplant 17:1681–1686. CrossRefGoogle Scholar
  7. 7.
    Hamel R, Dejarnac O, Wichit S et al (2015) Biology of Zika virus infection in human skin cells. J Virol 89:8880–8896. CrossRefGoogle Scholar
  8. 8.
    Petersen LR, Jamieson DJ, Powers AM, Honein MA (2016) Zika virus. N Engl J Med 374:1552–1563. CrossRefGoogle Scholar
  9. 9.
    Nascimento OJM, Da Silva IRF (2017) Guillain–Barré syndrome and Zika virus outbreaks. Curr Opin Neurol 30:500–507. CrossRefGoogle Scholar
  10. 10.
    De Oliveira Melo AS, Aguiar RS, Amorim MMR et al (2016) Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol 73:1407–1416. CrossRefGoogle Scholar
  11. 11.
    Lazear HM, Govero J, Smith AM et al (2016) A mouse model of Zika virus pathogenesis. Cell Host Microbe 19:720–730. CrossRefGoogle Scholar
  12. 12.
    Shresta S, Kyle JL, Snider HM et al (2004) Interferon-dependent immunity is essential for resistance to primary dengue virus infection in mice, whereas T- and B-cell-dependent immunity are less critical. J Virol 78:2701–2710. CrossRefGoogle Scholar
  13. 13.
    Grant A, Ponia SS, Tripathi S et al (2016) Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19:882–890. CrossRefGoogle Scholar
  14. 14.
    Bowen JR, Quicke KM, Maddur MS et al (2017) Zika virus antagonizes type I interferon responses during infection of human dendritic cells. PLoS Pathog 13:1–30. CrossRefGoogle Scholar
  15. 15.
    Kam Y-W, Leite JA, Lum F-M et al (2017) Specific biomarkers associated with neurological complications and congenital CNS abnormalities from Zika virus-infected patients in Brazil. J Infect Dis. Google Scholar
  16. 16.
    Tappe D, Pérez-Girón JV, Zammarchi L et al (2016) Cytokine kinetics of Zika virus-infected patients from acute to reconvalescent phase. Med Microbiol Immunol 205:269–273. CrossRefGoogle Scholar
  17. 17.
    Brubaker SW, Bonham KS, Zanoni I, Kagan JC (2016) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33:257CrossRefGoogle Scholar
  18. 18.
    Takeda K, Akira S (2003) Toll receptors and pathogen resistance. Cell Microbiol 5:143–153. CrossRefGoogle Scholar
  19. 19.
    Faye O, Faye O, Diallo D et al (2013) Quantitative real-time PCR detection of Zika virus and evaluation with field-caught mosquitoes. Virol J 10:1–8. CrossRefGoogle Scholar
  20. 20.
    Morris G, Barichello T, Stubbs B et al (2017) Zika virus as an emerging neuropathogen: mechanisms of neurovirulence and neuro-immune interactions. Mol Neurobiol. Google Scholar
  21. 21.
    Welte T, Reagan K, Fang H et al (2009) Toll-like receptor 7-induced immune response to cutaneous West Nile virus infection. J Gen Virol 90:2660–2668. CrossRefGoogle Scholar
  22. 22.
    Pierson T, Fremont D, Kuhn R, Diamond M (2013) Structural insights into the mechanisms of antibody-mediated neutralization of flavivirus infection: implications for vaccine development. Cell Host Microbe 17:148–159. Google Scholar
  23. 23.
    Ye J, Zhu B, Fu ZF et al (2013) Immune evasion strategies of flaviviruses. Vaccine 31:461–471. CrossRefGoogle Scholar
  24. 24.
    Luo H, Winkelmann ER, Fernandez-salas I et al (2018) Zika, dengue and yellow fever viruses induce differential anti-viral immune responses in human monocytic and first trimester trophoblast cells. Antivir Res 151:55CrossRefGoogle Scholar
  25. 25.
    Kawai T, Akira S (2011) Review toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650. CrossRefGoogle Scholar
  26. 26.
    Foo SS, Chen W, Chan Y et al (2017) Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy. Nat Microbiol 2:1558–1570. CrossRefGoogle Scholar
  27. 27.
    Araujo LM, Ferreira MLB, Nascimento OJM (2016) Síndrome de Guillain–Barré associada ao surto de infecção por vírus Zika no Brasil. Arq Neuropsiquiatr 74:253–255. CrossRefGoogle Scholar
  28. 28.
    Malkki H (2016) CNS infections: Zika virus infection could trigger Guillain–Barré syndrome. Nat Rev Neurol 12:187. CrossRefGoogle Scholar
  29. 29.
    Garcez P, Loiola E, Costa RM et al (2005) Zika virus impairs growth in human neurospheres and brain organoids. Am J Hum Genet 76:717–728. CrossRefGoogle Scholar
  30. 30.
    Chaudhary V, Yuen KS, Chan JF, Chan CP, Wang PH, Cai JP, Zhang S, Liang M, Kok KH, Chan CP, YuenKY Jin DY (2017) Selective activation of type II interferon signaling by Zika virus NS5 protein. J Virol. 91(14):e00163-17CrossRefGoogle Scholar
  31. 31.
    Laurent-Rolle M, Boer EF, Lubick KJ et al (2010) The NS5 protein of the virulent West Nile virus NY99 strain is a potent antagonist of type I interferon-mediated JAK-STAT signaling. J Virol 84:3503–3515. CrossRefGoogle Scholar
  32. 32.
    Lubick KJ, Robertson S, McNally K et al (2015) Flavivirus antagonism of type I interferon signaling reveals prolidase as a regulator of IFNAR1 surface expression. Cell Host Microbe 18:61–74. CrossRefGoogle Scholar
  33. 33.
    Xia H, Luo H, Shan C et al (2018) An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction. Nat Commun. Google Scholar
  34. 34.
    Ngono AE, Vizcarra EA, Tang W et al (2017) Mapping and role of the CD8+ T cell response during primary Zika virus infection in mice. Cell Host Microbe 21:35–46. CrossRefGoogle Scholar
  35. 35.
    Faria (2016) Zika virus in the Americas: early epidemiological and genetic findings. Science 352:345–349. CrossRefGoogle Scholar
  36. 36.
    Lanciotti RS, Lambert AJ, Holodniy M et al (2016) Phylogeny of Zika virus in western hemisphere, 2015. Emerg Infect Dis 22:933–935. CrossRefGoogle Scholar
  37. 37.
    Kumar A, Hou S, Airo AM et al (2016) Zika virus inhibits type-I interferon production and downstream signaling. EMBO Rep 17:1766–1775. CrossRefGoogle Scholar
  38. 38.
    Abdalla LF, Santos JHA, Barreto RTJ et al (2018) Atrial fibrillation in a patient with Zika virus infection. Virol J 15:4–9. CrossRefGoogle Scholar
  39. 39.
    Silasi M, Cardenas I, Racicot K et al (2015) Viral infections during pregnancy. Am J Reprod Immunol 73:199–213. CrossRefGoogle Scholar
  40. 40.
    Ornelas AM, Pezzuto P, Silveira PP, Melo FO, Ferreira TA, Oliveira-Szejnfeld PS, Leal JI, Amorim MM, Hamilton S, Rawlinson WD, Cardoso CC, Nixon DF, Tanuri A, Melo AS, Aguiar RS (2017) Immuneactivation in amniotic fluid from Zika virus-associated microcephaly. Ann Neurol 81(1):152–156CrossRefGoogle Scholar
  41. 41.
    Simoni M, Jurado KA, Abrahams VM et al (2017) Zika virus infection of Hofbauer cells. Am J ReprodImmunol 77:1–8Google Scholar
  42. 42.
    Barba-Spaeth G, Dejnirattisai W, Rouvinski A et al (2017) Structural basis of Zika and dengue virus potent antibody cross-neutralization. Nature 536:48–53CrossRefGoogle Scholar
  43. 43.
    Dejnirattisai W, Supasa P, Wongwiwat W et al (2016) Dengue virus sero-cross-reactivity drives antibodydependent enhancement of infection with zika virus. Nat Immunol 17:1102–1108CrossRefGoogle Scholar
  44. 44.
    Priyamvada L, Quicke KM, Hudson WH et al (2016) Human antibody responses after dengue virusinfection are highly cross-reactive to Zika virus. Proc Natl Acad Sci 113:7852–7857CrossRefGoogle Scholar
  45. 45.
    Bardina SV, Bunduc P, Tripathi S et al (2017) Enhancement of Zika virus pathogenesis by preexistingantiflavivirus immunity. Science 356:175–180CrossRefGoogle Scholar
  46. 46.
    Pantoja P, Pérez-Guzmán EX, Rodríguez IV et al (2017) Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus. Nat Commun. Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Marcelo Henrique Matias da Silva
    • 1
  • Raiza Nara Cunha Moises
    • 2
  • Brenda Elen Bizerra Alves
    • 1
    • 2
    • 3
  • Hannaly Wana Bezerra Pereira
    • 1
    • 2
    • 3
  • Anne Aline Pereira de Paiva
    • 2
    • 3
  • Ingryd Câmara Morais
    • 3
  • Yasmim Mesquita Nascimento
    • 2
    • 3
  • Joelma Dantas Monteiro
    • 2
    • 3
  • Janeusa Trindade de Souto
    • 1
    • 2
  • Manuela Sales Lima Nascimento
    • 4
  • Josélio Maria Galvão de Araújo
    • 1
    • 2
    • 3
  • Paulo Marcos Matta da Guedes
    • 1
    • 2
    Email author
  • José Veríssimo Fernandes
    • 1
    • 2
    Email author
  1. 1.Graduate Program in Parasitary Biology, Department of Microbiology and ParasitologyFederal University of Rio Grande do NorteNatalBrazil
  2. 2.Department of Microbiology and ParasitologyFederal University of Rio Grande do NorteNatalBrazil
  3. 3.Laboratory of Virology, Institute of Tropical MedicineFederal University of Rio Grande do NorteNatalBrazil
  4. 4.Edmond and Lily Safra International Institute of Neuroscience (ELS-IIN), Santos Dumont InstituteMacaíbaBrazil

Personalised recommendations