Letter | Published:

Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice


Zika virus (ZIKV) is an emerging, mosquito-borne RNA virus. The rapid spread of ZIKV within the Americas has unveiled microcephaly1 and Guillain–Barré syndrome2,3 as ZIKV-associated neurological complications. Recent reports have also indicated other neurological manifestations to be associated with ZIKV, including myelitis4, meningoencephalitis5 and fatal encephalitis6. Here, we investigate the neuropathogenesis of ZIKV infection in type I interferon receptor IFNAR knockout (Ifnar1−/−) mice, an infection model that exhibits high viral burden within the central nervous system. We show that systemic spread of ZIKV from the site of infection to the brain requires Ifnar1 deficiency in the haematopoietic compartment. However, spread of ZIKV within the central nervous system is supported by Ifnar1-deficient non-haematopoietic cells. Within this context, ZIKV infection of astrocytes results in breakdown of the blood–brain barrier and a large influx of CD8+ effector T cells. We also find that antiviral activity of CD8+ T cells within the brain markedly limits ZIKV infection of neurons, but, as a consequence, instigates ZIKV-associated paralysis. Taken together, our study uncovers mechanisms underlying ZIKV neuropathogenesis within a susceptible mouse model and suggests blood–brain barrier breakdown and T-cell-mediated neuropathology as potential underpinnings of ZIKV-associated neurological complications in humans.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

A correction to this article is available online at https://doi.org/10.1038/s41564-017-0101-7.

Change history

  • 08 January 2018

    In the version of this Letter originally published, technical problems led to errors in Figs. 3e and 4f. In Fig. 3e, the bottom right graph had an incorrect title of ‘CD8+ T cells’; it should have instead been ‘CD4+ T cells’. In Fig. 4f, the bottom panels had an incorrect title of ‘CD8 competent Ifnar–/–7 d.p.i. cerebral cortex’; it should have instead been ‘CD8 depleted Ifnar–/– 7 d.p.i. cerebral cortex’. These errors have now been corrected in all versions of the Letter.


  1. 1.

    Rasmussen, S. A., Jamieson, D. J., Honein, M. A. & Petersen, L. R. Zika virus and birth defects—reviewing the evidence for causality. New Engl. J. Med. 374, 1981–1987 (2016).

  2. 2.

    Cao-Lormeau, V. M. et al. Guillain–Barre syndrome outbreak associated with Zika virus infection in French Polynesia: a case–control study. Lancet 387, 1531–1539 (2016).

  3. 3.

    Oehler, E. et al. Zika virus infection complicated by Guillain–Barre syndrome—case report, French Polynesia, December 2013. Euro. Surveill. 19, 20720 (2014).

  4. 4.

    Mecharles, S. et al. Acute myelitis due to Zika virus infection. Lancet 387, 1481 (2016).

  5. 5.

    Carteaux, G. et al. Zika virus associated with meningoencephalitis. New Engl. J. Med. 374, 1595–1596 (2016).

  6. 6.

    Soares, C. N. et al. Fatal encephalitis associated with Zika virus infection in an adult. J. Clin. Virol. 83, 63–65 (2016).

  7. 7.

    Grant, A. et al. Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19, 882–890 (2016).

  8. 8.

    Lazear, H. M. et al. A mouse model of Zika virus pathogenesis. Cell Host Microbe 19, 720–730 (2016).

  9. 9.

    Dowall, S. D. et al. A susceptible mouse model for Zika virus infection. PLoS Negl. Trop. Dis. 10, e0004658 (2016).

  10. 10.

    Rossi, S. L. et al. Characterization of a novel murine model to study Zika virus. Am. J. Trop. Med. Hyg. 94, 1362–1369 (2016).

  11. 11.

    Elong Ngono, A. et al. Mapping and role of the CD8+ T cell response during primary Zika virus infection in mice. Cell Host Microbe 21, 35–46 (2017).

  12. 12.

    Iwasaki, A. Immune regulation of antibody access to neuronal tissues. Trends Mol. Med. 23, 227–245 (2017).

  13. 13.

    Daniels, B. P. et al. Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection. J. Clin. Invest. 127, 843–856 (2017).

  14. 14.

    Manangeeswaran, M., Ireland, D. D. & Verthelyi, D. Zika (PRVABC59) infection is associated with T cell infiltration and neurodegeneration in CNS of immunocompetent neonatal C57BL/6 mice. PLoS Pathog. 12, e1006004 (2016).

  15. 15.

    Winkler, C. W. et al. Adaptive immune responses to Zika virus are important for controlling virus infection and preventing infection in brain and testes. J. Immunol. 198, 3526–3535 (2017).

  16. 16.

    Cormier, S. A. et al. Limited type I interferons and plasmacytoid dendritic cells during neonatal respiratory syncytial virus infection permit immunopathogenesis upon reinfection. J. Virol. 88, 9350–9360 (2014).

  17. 17.

    Shaw, A. C., Goldstein, D. R. & Montgomery, R. R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 13, 875–887 (2013).

  18. 18.

    Sousa, A. Q. et al. Postmortem findings for 7 neonates with congenital Zika virus infection. Emerg. Infect. Dis. 23, 1164–1167 (2017).

  19. 19.

    Retallack, H. et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc. Natl Acad. Sci. USA 113, 14408–14413 (2016).

  20. 20.

    Dirlikov, E. et al. Guillain–Barre syndrome during ongoing Zika virus transmission—Puerto Rico, January 1–July 31, 2016. Morb. Mortal. Wkly Rep. 65, 910–914 (2016).

  21. 21.

    Yockey, L. J. et al. Vaginal exposure to Zika virus during pregnancy leads to fetal brain infection. Cell 166, 1247–1256.e4 (2016).

  22. 22.

    Van den Pol, A. N., Mao, G., Yang, Y., Ornaghi, S. & Davis, J. N. Zika virus targeting in the developing brain. J. Neurosci. 37, 2161–2175 (2017).

  23. 23.

    Iijima, N. & Iwasaki, A. Access of protective antiviral antibody to neuronal tissues requires CD4 T-cell help. Nature 533, 552–556 (2016).

Download references


The authors thank A.N. van den Pol for providing anti-ZIKV rat serum, and H. Dong and Y. Kumamoto for animal care and technical assistance, respectively. This study was in part supported by the National Institutes of Health (1R21AI131284 to A.I., T32GM007205 to L.J.Y. and 4T32AI007019-41 to K.A.J.). A.I. is an investigator of the Howard Hughes Medical Institute. K.A.J. is a recipient of the Burroughs Wellcome Postdoctoral Enrichment Program.

Author information

K.A.J. and A.I. planned the project, designed experiments, analysed and interpreted data and wrote the manuscript. K.A.J., P.W.W., S.L. and L.J.Y. designed and performed experiments. A.J.H. assisted with histopathological analysis.

Competing interests

The authors declare no competing financial interests.

Correspondence to Akiko Iwasaki.

Electronic supplementary material

Supplementary Information

Supplementary Figures 1–7.

Life Sciences Reporting Summary

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading

Fig. 1: Systemic spread of ZIKV is dependent upon Ifnar1−/− deficiency in the haematopoietic compartment.
Fig. 2: ZIKV infection of astrocytes is associated with breakdown of the BBB.
Fig. 3: ZIKV replication within the brain causes a large influx of CD8+ effector T cells.
Fig. 4: Antiviral activity of effector CD8+ T cells within the brain limits ZIKV replication within neurons, but instigates ZIKV-associated paralysis.