Zika Virus (ZIKV) is a mosquito-borne Flavivirus. Outbreaks across Southeast Asia and the Western Pacific have been reported over the past 10 years and case reports of associated Guillain-Barr syndrome have suggested that these virus strains may have pathological effects on neural tissue. The most recent migration of Zika into South and Central America has rapidly expanded the area of virus transmission. In addition, more than 400 cases have been reported in the US since late 2015, a number that continues to increase. This rise in transmission is of critical concern since infection with ZIKV during pregnancy is thought to lead to microcephaly and ocular abnormalities. It is still unknown how prenatal ZIKV brain infection leads to morphological abnormalities in the developing brain. Here we propose a multidisciplinary study using imaging, genetic fate mapping and in vivo neurodevelopmental approaches to study development of the murine neocortex in a precise and quantitative fashion. Our recent studies demonstrate that these techniques robustly measure critical cellular and molecular processes of fetal brain growth and function. We will leverage this expertise in collaboration with virus experts to determine the consequences of ZIKV infection on the developing brain in a model of known ZIKV susceptibility. We will determine which cells are most vulnerable to ZIKV and how infection of these cells translates to abnormal brain growth and intellectual disability.
Zika virus infection is rapidly expanding and is thought to cause fetal brain malformations although the details about fetal brain susceptibility and how the malformations progress have not been clearly determined. Here we will combine the use of a mouse model of fetal brain infection with genetic fate mapping and interferon administration to discover which fetal brain cells are vulnerable to infection, how this infection causes brain malformation, and whether manipulating the immune system at the cellular level may provide protection against microcephaly following ZIKV infection.
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