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

Abstract

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.

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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.

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.

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Acknowledgements

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.

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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.

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Correspondence to Akiko Iwasaki.

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

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Jurado, K.A., Yockey, L.J., Wong, P.W. et al. Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice. Nat Microbiol 3, 141–147 (2018). https://doi.org/10.1038/s41564-017-0060-z

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