Abstract

Congenital Zika virus (ZIKV) syndrome may cause fetal microcephaly in ~1% of affected newborns. Here, we investigate whether the majority of clinically inapparent newborns might suffer from long-term health impairments not readily visible at birth. Infection of immunocompetent pregnant mice with high-dose ZIKV caused severe offspring phenotypes, such as fetal death, as expected. By contrast, low-dose (LD) maternal ZIKV infection resulted in reduced fetal birth weight but no other obvious phenotypes. Male offspring born to LD ZIKV-infected mothers had increased testosterone (TST) levels and were less likely to survive in utero infection compared to their female littermates. Males also presented an increased number of immature neurons in apical and basal hippocampal dendrites, while female offspring had immature neurons in basal dendrites only. Moreover, male offspring with high but not very high (storm) TST levels were more likely to suffer from learning and memory impairments compared to females. Future studies are required to understand the impact of TST on neuropathological and neurocognitive impairments in later life. In summary, increased sex-specific vigilance is required in countries with high ZIKV prevalence, where impaired neurodevelopment may be camouflaged by a healthy appearance at birth.

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Data availability

Accession numbers of the ZIKV strains used to perform the phylogenetic analysis are indicated in Supplementary Fig. 1. The data that support the findings of this study are available from the corresponding author on request.

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Acknowledgements

The Heinrich Pette Institute, Leibniz Institute for Experimental Virology is supported by the Free and Hanseatic City of Hamburg and the Federal Ministry of Health. This study was supported by the Federal Ministry of Health (G.G.), the German Research Center for Infection (DZIF) (G.G.), the Niedersachsen-Research Network on Neuroinfectiology (N-RENNT) of the Ministry of Science and Culture of Lower Saxony, Germany (W.B., W.L.) and the German Federal Ministry of Education and Research (Infrafrontier grant 01KX1012) (M.H.A.). F.C.d.A. is supported by Deutsche Forschungsgemeinschaft (DFG) Grant (FOR 2419, CA1495/1-1 and CA 1495/4-1), ERA-NET Neuron Grant (Bundesministerium für Bildung und Forschung, BMBF, 01EW1410 ZMNH AN B1), Landesforschungsförderung Hamburg (Z-AN LF) and University Medical Center Hamburg-Eppendorf (UKE). R.B. is supported by the Deutsche Forschungsgemeinschaft (BA 1505/8-1). We are grateful for the excellent technical contribution of all staff at the technology platform small animal models of the Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg and the technical staff of the Department of Pathology, University of Veterinary Medicine, Hannover. We thank T. Andreas from the Department of Obstetrics and Fetal Medicine at the University Medical Center Hamburg-Eppendorf for his excellent technical support with the preparation of pregnant mice. We thank P. Pruunsild and H. Bading, Department of Neurobiology, Interdisciplinary Center for Neurosciences at Heidelberg University for providing human NPCs. We thank U. Markert, Department of Obstetrics, Placenta-Lab, University Hospital Jena for providing the human placental cells.

Author information

Affiliations

  1. Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany

    • Stephanie Stanelle-Bertram
    • , Kerstin Walendy-Gnirß
    • , Thomas Speiseder
    • , Swantje Thiele
    • , Ivy Asantewaa Asante
    • , Carola Dreier
    • , Nancy Mounogou Kouassi
    • , Annette Preuß
    • , Gundula Pilnitz-Stolze
    • , Ursula Müller
    • , Stefanie Thanisch
    •  & Gülsah Gabriel
  2. Neuronal Development, Center for Molecular Neurobiology Hamburg (ZNMH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • Melanie Richter
    • , Robin Scharrenberg
    •  & Froylan Calderon de Anda
  3. Research Group for Behavioral Biology, Center for Molecular Neurobiology Hamburg (ZNMH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • Vanessa Kraus
    • , Ronja Dörk
    • , Lynn Schau
    •  & Fabio Morellini
  4. Department of Pathology, University of Veterinary Medicine, Hannover, Germany

    • Vanessa Herder
    • , Ingo Gerhauser
    • , Vanessa Maria Pfankuche
    •  & Wolfgang Baumgärtner
  5. Center of Systems Neuroscience, Hannover, Germany

    • Vanessa Herder
    • , Vanessa Maria Pfankuche
    •  & Wolfgang Baumgärtner
  6. Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany

    • Christopher Käufer
    • , Inken Waltl
    •  & Wolfgang Löscher
  7. Department of Infectious Diseases, Molecular Virology, Heidelberg University, Heidelberg, Germany

    • Thais Moraes
    •  & Ralf Bartenschlager
  8. Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany

    • Julie Sellau
    • , Stefan Hoenow
    • , Jonas Schmidt-Chanasit
    • , Stephanie Jansen
    • , Daniel Cadar
    • , Hanna Lotter
    •  & Martin Gabriel
  9. German Centre for Infection Research (DZIF), Partner Site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany

    • Jonas Schmidt-Chanasit
    •  & Gülsah Gabriel
  10. Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • Benjamin Schattling
    •  & Manuel A. Friese
  11. Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • Harald Ittrich
  12. Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • Udo Bartsch
  13. Institute for Clinical and Laboratory Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • Thomas Renné
  14. Department of Obstetrics and Fetal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    • Petra Arck
  15. University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    • Olli Vapalahti
  16. Tropical Pathology and Infectious Disease Association, Cusco, Peru

    • Sany Benites
    •  & Lane Rolling
  17. Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany

    • Sabine M. Hölter
    •  & Oana Amarie
  18. German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany

    • Sabine M. Hölter
    • , Oana Amarie
    • , Helmut Fuchs
    •  & Martin Hrabe de Angelis
  19. Chair of Experimental Genetics, School of Life Science Weihenstephan, Technical University of Munich, Freising, Germany

    • Martin Hrabe de Angelis
  20. German Center for Diabetes Research (DZD), Neuherberg, Germany

    • Martin Hrabe de Angelis
  21. Center for Structural and Cell Biology in Medicine, University of Lübeck, Lübeck, Germany

    • Gülsah Gabriel
  22. University of Veterinary Medicine, Hannover, Germany

    • Gülsah Gabriel

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Contributions

G.G. conceived the study. S.S.-B. and G.G. designed and coordinated the experiments. S.S.-B., K.W.-G., C.D., A.P., G.P.-S., U.M. and S.Thi. performed all infection studies in mice. TST treatment of mice was performed by H.L., J.S. and S.H. S.Tha., I.A.A., T.S., N.M.K., C.D. and K.W.-G. performed the qRT–PCR assays. S.Tha., C.D., K.W.-G. and A.P. performed the hormone ELISA as well as the cytokine assays. T.R. measured the TST levels. V.H., W.B., V.M.P. and I.G. performed the histological and immunohistological examinations, TUNEL and cytokeratin staining, and the in situ hybridization and analysis. B.S. performed the Iba1 staining and respective analysis of fetal brains. H.I. performed the MRI scans on the brains of the offspring. M.R. performed Golgi staining and assisted with spine analysis. R.S. performed image acquisition, and the dendritic and spine analyses. F.C.d.A. coordinated the brain analysis. U.B. performed the immunohistochemical analyses of retinas. T.M. and R.B. performed the ZIKV replication kinetics in cell culture. Histopathological findings were analysed and discussed by P.A., M.A.F., V.H., I.G., V.M.P. and W.B. S.J. and T.S. measured viral IgG and IgM titres. D.C. performed the phylogenetic analysis. S.M.H., O.A., F.M., V.K., R.D., L.S., W.L., I.W. and C.K. performed and/or analysed the behavioural experiments. H.F. and M.H.d.A. coordinated and conceived the animal phenotypic tests. S.B. and L.R. were responsible for the recruitment of the mother–child cohort in Iquitos, Peru and for the qRT–PCR analysis of patient sera. J.S.-C., O.V. and M.G. provided material, analysed the data and discussed the study. S.S.-B. and G.G. wrote the manuscript. All authors revised the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Gülsah Gabriel.

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https://doi.org/10.1038/s41564-018-0236-1