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Introduction
First isolated in 1947 from the blood of a Rhesus monkey in the Zika forest, Uganda (Dick et al., 1952), Zika virus (ZIKV) was recently declared a global public health emergency by WHO (Heymann et al., 2016). After decades of confinement in Africa and Asia, the first large outbreak caused by the virus was recorded in French Polynesia in 2013 (Cao-Lormeau et al., 2014), leading to an unusual increase in the number of Guillain-Barré cases (Paixão et al., 2016). The current South-American epidemic which started in 2015 in Brazil revealed a strong correlation between infection with ZIKV and congenital angiotensin receptor blocker malformations, including microcephaly (Oliveira Melo et al., 2016).
Microcephaly is characterized by smaller head circumference, intellectual disability and seizures, and is due to reduced neuronal production or increased cell death (Barkovich et al., 2012). Recent data strongly supports the link between ZIKV and microcephaly, including detection of the virus in the amniotic fluid, placenta and brain of microcephalic fetuses, as well as in the blood of microcephalic newborns (Calvet et al., 2016; Mlakar et al., 2016; Martines et al., 2016). A retrospective study recently revealed a similar association between the French Polynesian 2013 outbreak and increased rates of microcephaly, supporting the implication of ZIKV (Cauchemez et al., 2016).
ZIKV belongs to the Flavivirus genus and is closely related to yellow fever virus (YFV), dengue virus (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV). Flaviviruses are arthropod-borne, single-stranded positive-sense RNA viruses, that cause infections in humans with a spectrum of clinical syndromes ranging from mild fever to hemorrhagic and encephalitic manifestations. Several infectious agents, belonging to the so-called TORCH complex, are responsible for congenital infections leading to brain developmental disorders, including microcephaly (Neu et al., 2015). However, neurotropic flaviviruses such as WNV and JEV, responsible for post-natal encephalitis, are rarely linked to congenital brain malformations, such as microcephaly (O\’Leary et al., 2006; Chaturvedi et al., 1980). Thus, neurovirulence of ZIKV in human fetuses must rely on mechanisms that are different from those involved in WNV or JEV neural infection, for example by infecting a particular set of fetal cells.
The cerebral cortex, a layered structure involved in higher cognitive functions, is strongly affected in microcephalic patients (Barkovich et al., 2012). During its normal development, all cortical neurons and most glial cells are generated, directly or indirectly, by the radial glial progenitor (RGP) cells (Kriegstein and Alvarez-Buylla, 2009). These cells are highly polarized and elongated, spanning the entire thickness of the developing neocortex. The apical process of RGP cells is in contact with the ventricular surface and the cerebro-spinal fluid (CSF), while their basal process is in contact with the pial surface and serves as a track for neuronal migration (Taverna et al., 2014). Genetic alterations leading to microcephaly are well known to affect RGP cell division, fate or survival (Fernández et al., 2016).
In vitro studies using induced Pluripotent Stem Cells (iPSCs)-derived brain cells, neurospheres and brain organoids have shown ZIKV infection of human neural stem and progenitor cells (Tang et al., 2016; Garcez et al., 2016; Qian et al., 2016; Dang et al., 2016). Recently, two different mouse models for ZIKV infection were developed and revealed a range of development defects including placental damage, developmental delay, ocular defects and embryonic death (Cugola et al., 2016; Miner et al., 2016). Another study described RGP cell infection and reduced cortical thickness after ZIKV injection into the lateral ventricle of embryonic brains (Li et al., 2016). It remains unclear if RGP cell infection was merely due to their location at the site of virus injection or if ZIKV has a specific tropism for these cells in the developing neocortex. This question is particularly important as it is still unknown if the virus reaches the developing brain via the cerebrospinal fluid (CSF), where ZIKV was detected (Rozé et al., 2016), or via blood vessels after crossing the placenta, as recently suggested (Miner et al., 2016). Another outstanding question is whether all flaviviruses share similar characteristics of infection in the developing brain, or if ZIKV, and especially microcephaly-associated ZIKV, exhibits a specific behavior in this tissue. In view of the rare congenital abnormalities associated with other flaviviruses, including following intrauterine WNV infection (O\’Leary et al., 2006), a comparative analysis between flaviviruses should provide a framework to identify ZIKV-specific mechanisms leading to microcephaly.