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

2018; Nature Portfolio; Volume: 24; Issue: 3 Linguagem: Inglês

10.1038/nm.4485

1546-170X

Kristina M. Adams Waldorf, Branden R. Nelson, Jennifer Stencel-Baerenwald, Colin Studholme, Raj P. Kapur, Blair Armistead, Christie L. Walker, Sean Merillat, Jay Vornhagen, Jennifer Tisoncik-Go, Audrey Baldessari, Michelle M. Coleman, Manjiri Dighe, Dennis Shaw, Justin A. Roby, Verónica Santana-Ufret, Erica Boldenow, Junwei Li, Xiaohu Gao, Michael A. Davis, Jesica Swanstrom, Kara Jensen, Douglas G. Widman, Ralph S. Baric, Joseph T. Medwid, Kathryn A. Hanley, Jason Ogle, Gillian Gough, Wonsok Lee, Chris English, W McIntyre Durning, Jeff Thiel, Chris Gatenby, Elyse C Dewey, Marian R. Fairgrieve, Rebecca D. Hodge, Richard Grant, LaRene Kuller, William B. Dobyns, Robert F. Hevner, Michael Gale, Lakshmi Rajagopal,

Viral Infections and Vectors

Zika virus infection of pregnant nonhuman primates results in the loss of fetal neuronal progenitor cells, even in the absence of overt microcephaly. 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.