Zika virus infection of neural stem cells to model pathogen-induced microcephaly

Duke University, Durham NC

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Abstract

Zika virus (ZIKV) is an RNA virus of the flavivirus genus that is causing an emerging global epidemic. ZIKV infection has been strongly associated with neurological disorders, including congenital microcephaly, in which brain size is severely reduced. Moreover the CDC has recently concluded that ZIKV causes microcephaly. The severity of ZIKV-associated microcephaly is suggestive of an early insult to brain development. In human microcephalic brains, ZIKV RNA has been detected in neurons and prospective glia. In mouse models of ZIKV infection, virus has also been detected in these same populations. ZIKV has also been shown to infect neural stem cells impacting their growth and survival. During early stages of fetal brain development, neural stem cells produce neurons and shift to glia production as development proceeds. Neural stem cell dysfunction is thought to be an underlying cause for genetic forms of microcephaly. Altogether this suggests a potential mechanism to explain why ZIKV infects both neurons and glia. In this proposal we will test the hypothesis that ZIKV infection targets embryonic neural stem cells, altering their cellular behavior and transcriptome. Using a novel set of assays developed in our labs, we will pursue two aims. First, we will determine how ZIKV impacts neural stem cells including production of new viable progeny. Second we will define the host mRNAs dynamically regulated by ZIKV infection in neural stem cells. Upon completion, these aims will elucidate a fundamental understanding of ZIKV biology, particularly within the developing nervous system, essential information for beginning to control the ZIKV epidemic.