Forebrain neural precursor cells are differentially vulnerable to zika virus infection

Abstract

Prenatal exposure to Zika virus (ZIKV) can result in microencephaly and congenital Zika syndrome, though some brain cells and structures are spared by the virus for unknown reasons. Here, a novel murine model of fetal ZIKV infection incorporating intraventricula infection and cell type specific in utero electroporation was used to identify the time course of ZIKV infection and to determine the identity of cells that are initially infected or spared during neocortical neurogenesis. In vivo time course studies revealed the presence of ZIKV in apical radial glial cells (aRGCs) at early time points following virus exposure, while basal intermediate progenitor cells (bIPCs) became maximally (ZIKV+) after 3 days of virus exposure. ZIKV infected fetal brains exhibited microencephaly as early as one day following infection, regardless of developmental age. This change in brain size was caused in part by apoptosis and reduced proliferation that persisted until birth. While 60% of aRGC basal fibers were perturbed during infection, 40% retained normal morphology, indicating that aRGCs are not uniformly vulnerable to ZIKV infection. To investigate this heterogeneous vulnerability, we performed genetic fate mapping using cell type-specific probes derived from a mouse E15.5 neocortical wall single cell RNA-Seq dataset. The results indicate that one class of aRGCs preferentially express the putative ZIKV entry receptor AXL, and that these cells are more vulnerable to ZIKV infection than other aRGC subtypes with low AXL expression. Together, these data uncover crucial temporal and cellular details of ZIKV fetal brain infection for prevention strategies and for management of congenital Zika syndrome.