Journal Article

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

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

2018

Overview

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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/100 / 13/31 / 13/51 / 14/19 / 38/77 / 38/90 / 59/57 / 631/326/596/2555 / 631/326/596/2557 / 631/378/2183 / 631/378/2571/2579 / 82/51 / 82/80 / adult / Animals / antibody-dependent enhancement / Biochemistry & Molecular Biology / Biomedicine / Brain / Brain injury / Cancer Research / Care and treatment / Cell Biology / Cells (biology) / Children / Cognition / dengue virus / Dentate gyrus / Development and progression / Disease Models, Animal / Epithelium / Female / Fetus - physiopathology / Fetus - virology / Fetuses / Flavivirus / Genetic disorders / Gliosis / Head injuries / Humans / immunity / Infections / Infectious Diseases / letter / Macaca nemestrina / Macaca nemestrina - virology / Medicine / Metabolic Diseases / Microcephaly / Microcephaly - diagnostic imaging / Microcephaly - physiopathology / Microcephaly - virology / Microencephaly / Molecular Medicine / Neural stem cells / Neurogenesis / Neurogenesis - genetics / Neuroimaging / Neurologi / Neurology / neurons / Neurosciences / Observations / Patterning / Pregnancy / Pregnancy Complications, Infectious - diagnostic imaging / Pregnancy Complications, Infectious - physiopathology / Pregnancy Complications, Infectious - virology / primate / Progenitor cells / progenitors / Research & Experimental / Subventricular zone / Temporal lobe / Teratogenicity / Ultrasound / vaccine / Vector-borne diseases / Viruses / Zika virus / Zika Virus - genetics / Zika Virus - pathogenicity / Zika virus infection / Zika Virus Infection - genetics / Zika Virus Infection - physiopathology / Zika Virus Infection - virology