Comparative Analysis Between Flaviviruses Reveals Specific Neural Stem Cell Tropism for Zika Virus in the Mouse Developing Neocortex

The recent Zika outbreak in South America and French Polynesia was associated with an epidemic of microcephaly, a disease characterized by a reduced size of the cerebral cortex. Other members of the Flavivirus genus, including West Nile virus (WNV), can cause encephalitis but were not demonstrated to cause microcephaly. It remains unclear whether Zika virus (ZIKV) and other flaviviruses may infect different cell populations in the developing neocortex and lead to distinct developmental defects. Here, we describe an assay to infect mouse E15 embryonic brain slices with ZIKV, WNV and dengue virus serotype 4 (DENV-4). We show that this tissue is able to support viral replication of ZIKV and WNV, but not DENV-4. Cell fate analysis reveals a remarkable tropism of ZIKV infection for neural stem cells. Closely related WNV displays a very different tropism of infection, with a bias towards neurons. We further show that ZIKV infection, but not WNV infection, impairs cell cycle progression of neural stem cells. Both viruses inhibited apoptosis at early stages of infection. This work establishes a powerful comparative approach to identify ZIKV-specific alterations in the developing neocortex and reveals specific preferential infection of neural stem cells by ZIKV.
Highlights • Mouse embryonic brain slices sustain Zika and West Nile, but not Dengue-4, virus replication. • Zika virus, but not West Nile virus, exhibits a selective tropism of infection for neural stem cells. • Zika virus, but not West Nile virus, alters cell cycle progression of neural stem cells. A Zika virus outbreak in South America is currently responsible for a large burst of microcephaly cases, a congenital brain malformation characterized by a reduced brain size. We describe here an assay to infect cultured mouse embryonic brain slices with Zika virus as well as other closely related flaviviruses not demonstrated to cause microcephaly. We show that Zika virus displays a specific pattern of infection in the developing brain, almost exclusively infecting neural stem cells. Zika virus impairs neural stem cell proliferation, an effect not seen for other flaviviruses and that may participate in the induction of microcephaly.