Nat Med. 2018 Mar;24(3):368-374. doi: 10.1038/nm.4485. Epub 2018 Feb 5.

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

Adams Waldorf KM^1,^2,^3,⁴, Nelson BR⁵, Stencel-Baerenwald JE^2,⁶, Studholme C^7,^8,⁹, Kapur RP^10,¹¹, Armistead B^3,¹², Walker CL¹, Merillat S¹², Vornhagen J^3,¹², Tisoncik-Go J^2,⁶, Baldessari A¹³, Coleman M^7,¹², Dighe MK⁹, Shaw DWW^9,¹⁴, Roby JA^2,⁶, Santana-Ufret V¹², Boldenow E^7,¹², Li J⁸, Gao X⁸, Davis MA^2,⁶, Swanstrom JA¹⁵, Jensen K¹⁵, Widman DG¹⁵, Baric RS^15,¹⁶, Medwid JT¹⁷, Hanley KA¹⁷, Ogle J¹³, Gough GM¹³, Lee W¹³, English C¹³, Durning WM¹³, Thiel J⁹, Gatenby C⁹, Dewey EC^2,⁶, Fairgrieve MR^2,⁶, Hodge RD¹⁸, Grant RF¹³, Kuller L¹³, Dobyns WB^5,⁷, Hevner RF⁵, Gale M Jr^2,^3,⁶, Rajagopal L^2,^3,^7,¹².

Author information

1: Department of Obstetrics & Gynecology, University of Washington, Seattle, Washington, USA.
2: Center for Innate Immunity and Immune Disease, University of Washington, Seattle, Washington, USA.
3: Department of Global Health, University of Washington, Seattle, Washington, USA.
4: Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
5: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, USA.
6: Department of Immunology, University of Washington, Seattle, Washington, USA.
7: Department of Pediatrics, University of Washington, Seattle, Washington, USA.
8: Department of Bioengineering, University of Washington, Seattle, Washington, USA.
9: Department of Radiology, University of Washington, Seattle, Washington, USA.
10: Department of Pathology, University of Washington, Seattle, Washington, USA.
11: Department of Pathology, Seattle Children's Hospital, Seattle, Washington, USA.
12: Center for Global Infectious Disease Research, Seattle Children's Research Institute, Seattle, Washington, USA.
13: Washington National Primate Research Center, Seattle, Washington, USA.
14: Department of Radiology, Seattle Children's Hospital, Seattle, Washington, USA.
15: Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
16: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
17: Department of Biology, New Mexico State University, Las Cruces, New Mexico, USA.
18: Allen Institute for Brain Science, Seattle, Washington, USA.

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.