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Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain

Nature Medicine volume 24, pages 368–374 (2018)Cite this article

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Abstract

Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth.

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Figure 1: Fetal brain MRI imaging and volume analysis.
Figure 2: Neuropathology of the fetal brain demonstrating ZIKV-associated ependymal fusion and periventricular gliosis.
Figure 3: NSC proliferation is reduced in late fetal neurogenic zones.
Figure 4: Attenuated neurogenesis in late fetal neurogenic zones accompanied by granule neuron dysmorphia in the dentate gyrus after maternal ZIKV infection.

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Acknowledgements

We would like to acknowledge J. Hamanishi for technical assistance with preparation of the figures. We acknowledge V. Alishetti for technical assistance and G. Hess for technical advice related to the flow cytometry studies. We thank M. Diamond (Washington University) for the kind gift of antibodies (ZV-13, Supplementary Table 5). We also thank S. Rodriguez and I. Hansen in the New Mexico State University Biology Department for mosquito rearing. We thank C. Hughes and G. Gallardo for administrative assistance.

This work was primarily supported by generous private philanthropic gifts, mainly from five donors in Florida, who wish to remain anonymous. Further support was obtained from the University of Washington Department of Obstetrics & Gynecology, Seattle Children's Research Institute and the National Institutes of Health (NIH), grant no. R01AI100989 (L.R. and K.M.A.W.), AI083019 (M.G.), AI104002 (M.G.), AI100625 (R.S.B.), AI107731 (R.S.B.), R01NS092339 (R.F.H.), R01NS085081 (R.F.H.), R21OD023838 (B.R.N.), and the Keck Foundation (B.R.N.). The NIH training grants T32 HD007233 (principal investigator: L. Frenkel) and T32 AI07509 (principal investigator: L. Campbell) supported E.B. and J.V., respectively. A Perkins Coie Award for Discovery supported J.A.R. The NIH Office of Research Infrastructure Programs (P51 OD010425) also supported this project. The authors thank the Allen Institute for Brain Science founders, P. Allen and J. Allen, for their vision, encouragement and support.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funders. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. Branden R Nelson, Jennifer E Stencel-Baerenwald, Colin Studholme, Raj P Kapur, Blair Armistead, Christie L Walker, Sean Merillat, Jay Vornhagen and Jennifer Tisoncik-Go: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington, USA

    Kristina M Adams Waldorf & Christie L Walker

  2. Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA

    Kristina M Adams Waldorf, Jennifer E Stencel-Baerenwald, Jennifer Tisoncik-Go, Justin A Roby, Michael A Davis, Elyse C Dewey, Marian R Fairgrieve, Michael Gale Jr & Lakshmi Rajagopal

  3. Department of Global Health, University of Washington, Seattle, Washington, USA

    Kristina M Adams Waldorf, Blair Armistead, Jay Vornhagen, Michael Gale Jr & Lakshmi Rajagopal

  4. Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

    Kristina M Adams Waldorf

  5. Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA

    Branden R Nelson, William B Dobyns & Robert F Hevner

  6. Department of Immunology, University of Washington, Seattle, Washington, USA

    Jennifer E Stencel-Baerenwald, Jennifer Tisoncik-Go, Justin A Roby, Michael A Davis, Elyse C Dewey, Marian R Fairgrieve & Michael Gale Jr

  7. Department of Pediatrics, University of Washington, Seattle, Washington, USA

    Colin Studholme, Michelle Coleman, Erica Boldenow, William B Dobyns & Lakshmi Rajagopal

  8. Department of Bioengineering, University of Washington, Seattle, Washington, USA

    Colin Studholme, Junwei Li & Xiaohu Gao

  9. Department of Radiology, University of Washington, Seattle, Washington, USA

    Colin Studholme, Manjiri K Dighe, Dennis W W Shaw, Jeff Thiel & Chris Gatenby

  10. Department of Pathology, University of Washington, Seattle, Washington, USA

    Raj P Kapur

  11. Department of Pathology, Seattle Children's Hospital, Seattle, Washington, USA

    Raj P Kapur

  12. Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA

    Blair Armistead, Sean Merillat, Jay Vornhagen, Michelle Coleman, Veronica Santana-Ufret, Erica Boldenow & Lakshmi Rajagopal

  13. Washington National Primate Research Center, Seattle, Washington, USA

    Audrey Baldessari, Jason Ogle, G Michael Gough, Wonsok Lee, Chris English, W McIntyre Durning, Richard F Grant & LaRene Kuller

  14. Department of Radiology, Seattle Children's Hospital, Seattle, Washington, USA

    Dennis W W Shaw

  15. Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Jesica A Swanstrom, Kara Jensen, Douglas G Widman & Ralph S Baric

  16. Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    Ralph S Baric

  17. Department of Biology, New Mexico State University, Las Cruces, New Mexico, USA

    Joseph T Medwid & Kathryn A Hanley

  18. Allen Institute for Brain Science, Seattle, Washington, USA

    Rebecca D Hodge

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Contributions

K.M.A.W., B.R.N., J.E.S.-B., R.P.K., C.S., R.S.B., D.G.W., M.G. and L.R. designed the study. K.M.A.W., B.R.N., J.E.S.-B., R.P.K., C.S., R.P.K., B.A., S.M., J.T.-G., A.B., M.C., J.A.R., J.V., V.S.-U., E.B., J.A.S., J.L., M.A.D., K.J., D.G.W., J.T.M., K.A.H., J.O., G.M.G., W.L., C.E., W.M.D., C.G., E.C.D., M.R.F., L.K. and L.R. performed the experiments. K.M.A.W., B.R.N., J.E.S.-B., C.S., R.P.K., B.A., C.L.W., S.M., J.T.-G., A.B., M.K.D., D.W.W.S., J.A.R., J.V., J.L., X.G., M.A.D., J.A.S., K.J., R.S.B., R.D.H., R.F.G., W.B.D., R.H., L.R., R.F.H., M.G. and L.R. analyzed the data. K.M.A.W., B.R.N., J.E.S.-B., C.S., R.P.K., B.A., C.L.W., A.B., W.B.D., M.G. and L.R. drafted the manuscript. All authors reviewed the final draft of the manuscript.

Corresponding authors

Correspondence to Kristina M Adams Waldorf, Michael Gale Jr or Lakshmi Rajagopal.

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Adams Waldorf, K., Nelson, B., Stencel-Baerenwald, J. et al. Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain. Nat Med 24, 368–374 (2018). https://doi.org/10.1038/nm.4485

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