br Dr Takao received the

Dr. Takao received the Ministry of Health, Labour, and Welfare of Japan JSPS KAKENHI, Grant-in-Aid for Scientific Research (C; 26430060) JSPS KAKENHI Grant Number JP 16H06277. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was financially supported by grants for Scientific Research from the Ministry of Health, Labour and Welfare of Japan.
Introduction The current (2015–2016) Zika virus (ZIKV) epidemic in South America and in the Caribbean islands revealed the lack of knowledge on the pathophysiological mechanisms of a virus discovered almost 70years ago in Uganda (Dick et al., 1952). This arbovirus is transmitted by vectors from the Aedes family, in particular Aedes aegypti and Aedes albopictus. Phylogenetic analyses revealed recently that three lineages (one Asian and two Africans) exist and explain the PD184352 of ZIKV over the last 70years (Shen et al., 2016; Gong et al., 2016). The current epidemic is due to ZIKV from the Asian lineage, even though some further genetic evolution seems to have occurred (Wang et al., 2016). While a large proportion of infected persons are asymptomatic (70–80%), others develop rather classical clinical signs of an arboviral infection namely, skin rash, headache, myalgia, joint pain, conjunctivitis, but also moderate fever. In some cases, neurological disorders have been linked to ZIKV infections, in particular Guillain-Barré syndrome (GBS), myelitis, encephalitis, neuralgia and microcephaly in newborns and infants born to women with ZIKV infection during pregnancy (Musso et al., 2016). Microcephaly is now well documented as a direct disorder triggered by ZIKV infection, as the virus can cross the placenta (Miner et al., 2016), is found in the amniotic fluid (Calvet et al., 2016) and can be detected in post-mortem newborn brains (Brasil Martines et al., 2016). In particular, infection during the first trimester of pregnancy has been proposed to lead to microcephaly in 1% of cases (Cauchemez et al., 2016). Studies on animal models (rodent) show that ZIKV can cause a similar pathology as in humans, such as trans-placental fetal transmission and neurological impairment in fetal and adult brain (Rossi et al., 2016; Dowall et al., 2016; Aliota et al., 2016; Cugola et al., 2016; Lazear et al., 2016; Miner et al., 2016). However, most of these models are based on an immunodeficient background. Recent reports clearly demonstrate that ZIKV can infect human and murine neural precursors. Ex vivo works using induced pluripotent cells (IPSc)-derived neural precursors cells (NPCs) and neural stem cells (NSCs) show that ZIKV has a preferential tropism for cells of the neuronal lineage during development (Tang et al., 2016; Qian et al., 2016; Garcez et al., 2016). Notably, some reports suggest that impairment of proliferation and cell death is associated with ZIKV infection (Tang et al., 2016; Li et al., 2016), whereas another report suggests that ZIKV poorly stimulates immune response and cytopathic effect in human neuroprecursors obtained from fetal tissue (Hanners et al., 2016). This lack of strong immune response would allow ZIKV to persist during development and is consistent with the replication seen over few weeks in this tissue. These observations are strengthening the hypothesis that infection early during brain development can have drastic effects. While most of the focus has been directed to Asian ZIKV strains or to African MR-766, much less effort has been undertaken to monitor potential circulating ZIKV of the African lineage (Grard et al., 2014; Baraka and Kweka, 2016; Meda et al., 2016). In this context, there is an urgent need to have clear understanding of the pathophysiological mechanisms involved in infection by African ZIKV, in particular in terms of neurovirulence. In other words, to know whether the neurological effects observed with the Asian lineage are specifically associated with the Asian strain, in terms of severity and specificity, or if we can expect African strains to lead to similar disorders. So far, most of the studies that investigated African ZIKV strain used the original strain of ZIKV (MR-766, isolated in 1947). Lately, criticisms emerged concerning the pertinence of this strain, isolated from primates and extensively amplified in suckling mouse brains and ex vivo on cells (Haddow et al., 2012; Musso et al., 2016).