Zika virus (ZIKV) is associated with brain development abnormalities such as primary microcephaly, a severe reduction in brain growth. Here we demonstrated in vivo the impact of congenital ZIKV infection in blood vessel development, a crucial step in organogenesis. ZIKV was injected intravenously in the pregnant type 2 interferon (IFN)-deficient mouse at embryonic day (E) 12.5. The embryos were collected at E15.5 and postnatal day (P)2. Immunohistochemistry for cortical progenitors and neuronal markers at E15.5 showed the reduction of both populations as a result of ZIKV infection. Using confocal 3D imaging, we found that ZIKV infected brain sections displayed a reduction in the vasculature density and vessel branching compared to mocks at E15.5; altogether, cortical vessels presented a comparatively immature pattern in the infected tissue. These impaired vascular patterns were also apparent in the placenta and retina. Moreover, proteomic analysis has shown that angiogenesis proteins are deregulated in the infected brains compared to controls. At P2, the cortical size and brain weight were reduced in comparison to mock-infected animals. In sum, our results indicate that ZIKV impairs angiogenesis in addition to neurogenesis during development. The vasculature defects represent a limitation for general brain growth but also could regulate neurogenesis directly.

In the last few months, an overwhelming number of people have been exposed to the Zika virus (ZIKV) in South and Central America. Here we showed, in vitro, that a Brazilian isolate impacts more severely murine neuronal progenitors and neurons than the African strain MR766. We found that the Brazilian isolate more pronouncedly inhibits neurite extension from neurospheres, alters their differentiation potential and causes neurons to have less and shorter processes. Comparing both lineages using a panel of inflammatory cytokines, we showed, with human neuroblastoma cells, that ZIKV induces the production of several inflammatory and chemotactic cytokines and once again, the Brazilian isolate had a more significant impact. Although much more needs to be studied regarding the association of ZIKV infection and brain damage during development, our study sheds some light into the differences between African and American lineages and the mechanisms by which the virus may be affecting neurogenesis.