Skip to main content

Advertisement

Log in

Innate immune response in patients with acute Zika virus infection

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Hayes EB (2009) Zika virus outside Africa. Emerg Infect Dis 15:1347–1350. https://doi.org/10.3201/eid1509.090442

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1371/journal.pntd.0004726

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1007/s00705-015-2695-5

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1590/0074-02760150192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/S1473-3099(16)00095-5

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1111/ajt.14333

    Article  Google Scholar 

  7. Hamel R, Dejarnac O, Wichit S et al (2015) Biology of Zika virus infection in human skin cells. J Virol 89:8880–8896. https://doi.org/10.1128/JVI.00354-15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Petersen LR, Jamieson DJ, Powers AM, Honein MA (2016) Zika virus. N Engl J Med 374:1552–1563. https://doi.org/10.1056/NEJMra1602113

    Article  CAS  PubMed  Google Scholar 

  9. Nascimento OJM, Da Silva IRF (2017) Guillain–Barré syndrome and Zika virus outbreaks. Curr Opin Neurol 30:500–507. https://doi.org/10.1097/WCO.0000000000000471

    Article  PubMed  Google Scholar 

  10. De Oliveira Melo AS, Aguiar RS, Amorim MMR et al (2016) Congenital Zika virus infection: beyond neonatal microcephaly. JAMA Neurol 73:1407–1416. https://doi.org/10.1001/jamaneurol.2016.3720

    Article  Google Scholar 

  11. Lazear HM, Govero J, Smith AM et al (2016) A mouse model of Zika virus pathogenesis. Cell Host Microbe 19:720–730. https://doi.org/10.1016/j.chom.2016.03.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1128/JVI.78.6.2701-2710.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.chom.2016.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1371/journal.ppat.1006164

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1093/neuonc/nox188/4265638

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s00430-015-0445-7

    Article  CAS  PubMed  Google Scholar 

  17. Brubaker SW, Bonham KS, Zanoni I, Kagan JC (2016) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33:257

    Article  Google Scholar 

  18. Takeda K, Akira S (2003) Toll receptors and pathogen resistance. Cell Microbiol 5:143–153. https://doi.org/10.1046/j.1462-5822.2003.00264.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1186/1743-422X-10-311

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1007/s12035-017-0635-y

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1099/vir.0.011783-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s10461-012-0143-z.Provider-patient

    Article  Google Scholar 

  23. Ye J, Zhu B, Fu ZF et al (2013) Immune evasion strategies of flaviviruses. Vaccine 31:461–471. https://doi.org/10.1016/j.vaccine.2012.11.015

    Article  CAS  PubMed  Google Scholar 

  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 151:55

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.immuni.2011.05.006

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/s41564-017-0016-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1590/0004-282X20160035

    Article  PubMed  Google Scholar 

  28. Malkki H (2016) CNS infections: Zika virus infection could trigger Guillain–Barré syndrome. Nat Rev Neurol 12:187. https://doi.org/10.1038/nrneurol.2016.30

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1086/429930

    Article  Google Scholar 

  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):e00163-17

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1128/JVI.01161-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1097/RCT.0000000000000239.Texture

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xia H, Luo H, Shan C et al (2018) An evolutionary NS1 mutation enhances Zika virus evasion of host interferon induction. Nat Commun. https://doi.org/10.1038/s41467-017-02816-2

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s10549-015-3663-1.Progestin

    Article  PubMed Central  Google Scholar 

  35. Faria (2016) Zika virus in the Americas: early epidemiological and genetic findings. Science 352:345–349. https://doi.org/10.1126/science.aaf5036.Zika

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lanciotti RS, Lambert AJ, Holodniy M et al (2016) Phylogeny of Zika virus in western hemisphere, 2015. Emerg Infect Dis 22:933–935. https://doi.org/10.3201/eid2205.160065

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.15252/embr.201642627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Abdalla LF, Santos JHA, Barreto RTJ et al (2018) Atrial fibrillation in a patient with Zika virus infection. Virol J 15:4–9. https://doi.org/10.1186/s12985-018-0938-2

    Article  Google Scholar 

  39. Silasi M, Cardenas I, Racicot K et al (2015) Viral infections during pregnancy. Am J Reprod Immunol 73:199–213. https://doi.org/10.1111/aji.12355.VIRAL

    Article  PubMed  PubMed Central  Google Scholar 

  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):152–156

    Article  CAS  PubMed  Google Scholar 

  41. Simoni M, Jurado KA, Abrahams VM et al (2017) Zika virus infection of Hofbauer cells. Am J ReprodImmunol 77:1–8

    Google Scholar 

  42. Barba-Spaeth G, Dejnirattisai W, Rouvinski A et al (2017) Structural basis of Zika and dengue virus potent antibody cross-neutralization. Nature 536:48–53

    Article  Google Scholar 

  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 17:1102–1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 113:7852–7857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bardina SV, Bunduc P, Tripathi S et al (2017) Enhancement of Zika virus pathogenesis by preexistingantiflavivirus immunity. Science 356:175–180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1038/ncomms15674

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Paulo Marcos Matta da Guedes or José Veríssimo Fernandes.

Ethics declarations

Conflict of interest

The authors have no conflicts of interest to declare.

Additional information

Edited by: Stipan Jonjic.

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

da Silva, M.H.M., Moises, R.N.C., Alves, B.E.B. et al. Innate immune response in patients with acute Zika virus infection. Med Microbiol Immunol 208, 703–714 (2019). https://doi.org/10.1007/s00430-019-00588-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-019-00588-8

Keywords

Navigation