Abstract

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.

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Acknowledgements

We thank the Veterinary Services, Colony Management, Scientific Protocol Implementation, and Pathology Services staff at the WNPRC for their contribution to this study. We thank M. Harke, K. Brunner, T. Frost, M. Schotzko, W. Newton, K. Antony, S. Kohn, C. Newman, L. Stewart, M. Koenig, M. Breitbach, and M. Mohns for technical assistance and for monitoring the ZIKV-infected pregnant animals at WNPRC. We thank J. Eickhoff for help with statistical analysis. We thank T. Morgan for help with interpreting pathology. Studies at WNPRC were supported by DHHS/PHS/NIH R01Al116382-01A1 to D.H.O. and by the Pediatric Infectious Diseases Society to E.L.M. We thank E. Kallas for providing information on 2016 live-birth rates in Brazil. This work was also supported in part by the Office of Research Infrastructure Programs/OD grant (P51OD011106) awarded to WNPRC, Madison–Wisconsin. This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grants RR15459-01 and RR020141-01. The studies at CNPRC were supported by a CNPRC pilot research grant, 1R21AI129479-01 (K.K.V.R.), the Office of Research Infrastructure Programs/OD (P51OD011107) (CNPRC), FDA contract HHSF223201610542P (L.L.C.) and start-up funds from the Pathology, Microbiology and Immunology Department to L.L.C. We thank V. Bakula, I. Cazares, M. Christensen, C. Cruzen, A. Gibbons, D. Lemos, A. Singapuri, J. Usachenko, W. von Morgenland, J. Watanabe, J. Yee, A. Murphy, and the staff of Clinical Labs, Veterinary and Colony Research Services for technical assistance. Work at the ONPRC was supported by the National Institutes of Health Office of Research Infrastructure Programs grant (P51OD011092) to ONPRC and R21HD091032 to D.N.S. We thank L. Drew Martin, B. Dozier and N. Sternberger for their veterinary expertise, and the dedicated staff in the ONPRC Department of Comparative Medicine for assistance with animal care. The studies at Tulane National Primate Research Center (TNPRC) were supported by NIH grant R01 AI099795-05 to X.W. and by the National Institutes of Health Office of Research Infrastructure Program grant (P51OD011104) to TNPRC. We thank F. Schiro, R. Blair, and P. Aye for technical assistance. At WaNPRC, the work was primarily supported by generous private philanthropic gifts, including those from five donors from Florida who wish to remain anonymous. Further support was obtained from the University of Washington Department of Obstetrics & Gynecology, the Seattle Children’s Research Institute, and National Institutes of Health grants R01AI100989 (L.R. and K.A.W.), AI083019 (M.G.), and AI104002 (M.G.). The National Institutes of Health Office of Research Infrastructure Programs (P51 OD010425) also supported this project. We thank J. Ogle, W. Lee, and J. Thiel for technical assistance in monitoring the animals. Work at SNPRC was supported by NIH grants R01HL105704 and R21AI129455 (C.Y.C.), National Institutes of Health Office of Research Infrastructure Programs grant P51 ODOD011133 to SNPRC, and the Texas Biomedical Research Institute. We thank D. Layne-Colon for marmoset pregnancy management, ultrasonography, and collection and processing of placental and fetal material. We also thank S. Davis for technical support; M. Suter for guidance in the placental studies and analysis; and X. de Lamballerie (European Virus Archive) and B. Russell (CDC) for providing ZIKV strains.

Author information

Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Wisconsin–Madison, Madison, WI, USA

    • Dawn M. Dudley
    •  & David H. O’Connor
  2. California National Primate Research Center, University of California–Davis, Davis, CA, USA

    • Koen K. Van Rompay
    • , Amir Ardeshir
    • , Rebekah I. Keesler
    •  & Eliza Bliss-Moreau
  3. Department of Pathology, Microbiology, and Immunology, University of California–Davis, Davis, CA, USA

    • Koen K. Van Rompay
    •  & Lark L. Coffey
  4. Department of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Portland, OR, USA

    • Peta L. Grigsby
    •  & Rosemary J. Steinbach
  5. Vaccine and Gene Therapy Institute, Oregon Health and Science University, Portland, OR, USA

    • Alec J. Hirsch
    •  & Daniel N. Streblow
  6. Division of Pathobiology and Immunology, Oregon National Primate Research Center, Portland, OR, USA

    • Alec J. Hirsch
    •  & Daniel N. Streblow
  7. Division of Comparative Medicine, Oregon National Primate Research Center, Portland, OR, USA

    • Rhonda P. MacAllister
    •  & Travis Hodge
  8. Pathology Services Unit, Division of Comparative Medicine, Oregon National Primate Research Center, Portland, OR, USA

    • Heidi L. Pecoraro
    •  & Lois M. Colgin
  9. Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX, USA

    • Suzette Tardif
  10. Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX, USA

    • Jean L. Patterson
    •  & Manasi Tamhankar
  11. Departments of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, USA

    • Maxim Seferovic
    •  & Kjersti M. Aagaard
  12. Department of Molecular and Human Genetics at Baylor College of Medicine, Houston, TX, USA

    • Kjersti M. Aagaard
  13. Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA

    • Claudia Sánchez-San Martín
    •  & Charles Y. Chiu
  14. Department of Medicine/Infectious Diseases, University of California, San Francisco, San Francisco, CA, USA

    • Charles Y. Chiu
  15. Division of Microbiology, Tulane National Primate Research Center, New Orleans, LA, USA

    • Antonito T. Panganiban
    •  & Nicholas J. Maness
  16. Department of Microbiology and Immunology, Tulane University Health Sciences Center, New Orleans, LA, USA

    • Antonito T. Panganiban
  17. Division of Comparative Pathology, Tulane National Primate Research Center, New Orleans, LA, USA

    • Ronald S. Veazey
    •  & Xiaolei Wang
  18. Division of Veterinary Medicine, Tulane National Primate Research Center, New Orleans, LA, USA

    • Margaret H. Gilbert
    •  & Rudolf P. Bohm
  19. Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA

    • Kristina M. Adams Waldorf
  20. Department of Immunology, University of Washington, Seattle, WA, USA

    • Michael Gale Jr
  21. Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, USA

    • Michael Gale Jr
  22. Department of Pediatrics, University of Washington, Seattle, WA, USA

    • Lakshmi Rajagopal
  23. Center for Global Infectious Disease Research, Seattle Children’s Research Institute, Seattle, WA, USA

    • Lakshmi Rajagopal
  24. Washington National Primate Research Center, University of Washington, Seattle, WA, USA

    • Charlotte E. Hotchkiss
  25. Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI, USA

    • Emma L. Mohr
  26. Wisconsin National Primate Research Center, University of Wisconsin–Madison, Madison, WI, USA

    • Saverio V. Capuano III
    • , Heather A. Simmons
    • , Andres Mejia
    • , Thomas C. Friedrich
    • , Thaddeus G. Golos
    •  & David H. O’Connor
  27. Department of Pathobiological Sciences, University of Wisconsin–Madison, Madison, WI, USA

    • Thomas C. Friedrich
  28. Department of Comparative Biosciences and Obstetrics and Gynecology, University of Wisconsin–Madison, Madison, WI, USA

    • Thaddeus G. Golos

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Contributions

D.M.D., D.H.O., T.C.F., E.L.M., K.K.V.R., L.L.C., P.L.G., D.N.S., A.J.H., J.L.P., S.T., M.S., K.M.A., C.Y.C., X.W., R.S.V., K.M.A.W., M.G., L.R., N.J.M., A.T.P., M.H.G., and R.P.B. designed experiments. D.M.D., K.K.V.R., L.L.C., A.A., P.L.G., R.J.S., D.N.S., A.J.H., J.L.P., M.T., M.S., K.M.A., C.S.-S.M., C.Y.C., X.W., K.M.A.W., M.G., L.R., R.S.V., N.J.M., A.T.P., A.M., and H.A.S. analyzed data. D.M.D., E.L.M., T.G.G., T.C.F., S.V.C., K.K.V.R., L.L.C., R.J.S., M.S., S.T., K.M.A., C.Y.C., K.M.A.W., M.G., and A.T.P. drafted the manuscript. S.V.C., R.P.M., T.H., M.H.G., and R.P.B. were part of the veterinary staff who monitored the nonhuman primates. S.V.C., T.H., and C.E.H. collected data from breeding-colony records. R.I.K., H.L.P., L.M.C., E.B.-M., H.A.S., and A.M. provided pathology assistance. E.L.M., A.A., and R.J.S. managed projects. There is one representative corresponding author per NPRC involved in this article. The publication’s contents are solely the responsibility of the authors and do not necessarily represent the official views of NCRR or NIH.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Koen K. Van Rompay or Daniel N. Streblow or Suzette Tardif or Antonito T. Panganiban or Kristina M. Adams Waldorf or David H. O’Connor.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figure 1 and Supplementary Tables 1, 2, 4 and 5

  2. Reporting Summary

  3. Supplementary Table 3

    Per-animal data collected from each primate research center used in data analysis for this study

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DOI

https://doi.org/10.1038/s41591-018-0088-5