Alice Tran

Introduction: Human ZIKV infection, historically known as a mild, self-limiting arboviral illness circulating in Africa and Southeast Asia via Aedes mosquito bites, has emerged as a cause of severe neurological damage as it has spread to the Americas (Reynolds 2017). Post-2013 ZIKV outbreaks have been found to cause a wide range of neurological consequences including Guillan-Barre Syndrome after adult infection and permanent, severe fetal CNS malformations after intrauterine transmission during the first two trimesters of pregnancy (Li 2016, Retallack 2016, Song 2017). Because the mechanistic basis of ZIKV pathogenesis remains poorly understood, there is no effective treatment for infection and the only recommended strategy for prevention of infection remains avoiding mosquito bites. Methods: Challenges to understanding ZIKV pathogenesis include technical obstacles of examining an intrauterine CNS disease process involving temporally and spatially regulated signaling between multiple differentiating cell populations in a growing, folding 3D environment. An emerging tool for overcoming such technical limitations has been the use of induced human pluripotent stem cells (Kelava 2016) and the development of increasingly refined human stem cell-derived cerebral organoids (Lancaster 2013, Qian 2016). Results: Non-exclusive mechanisms proposed to explain how ZIKC depletes NPCs include NPC cell death (Retallack 2016) due to induction of local neuroinflammation (Lum 2017), ZIKV-mediated dysregulation of pro-apoptotic signaling (Souza 2016, Dang 2016), and ZIKV-mediated dysregulation of cell cycle progression (Gabriel 2017). Conclusion: A growing body of evidence suggests fetal ZIKV infection causes microcephaly by selectively infecting and depleting neuroprogenitor cells (NPCs) in the developing CNS. Use of human iPSC and cerebral organoid models will be helpful in much-needed further inquiry into the precise underlying pathogenic mechanisms of fetal ZIKV infection, including characterization of viral virulence and host susceptibility factors, clinical course of maternal and fetal infection, and development of more sensitive and effective detection and antiviral treatment for maternal infection.

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