Innate immunity in Zika Virus infection and neurogenesis deficits

August 2020
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Zika virus (ZIKV) outbreaks and their strong link to microcephaly have raised public health concerns globally. Clinical and animal studies have shown that miscarriage and brain malformation are more frequent when infection occurs during early pregnancy. ZIKV-associated microcephaly is most likely due to the high susceptibility of neural stem/progenitor cells (NS/PCs), the origin of the brain, to ZIKV. Microglia are the first and major innate immune defenders of the brain. They arise exclusively from the progenitor cells in the embryonic yolk sac (YS) and migrate to the fetal brain during a restricted time window. Microglia from the brain are able to transmit the virus to NS/PCs and induce apoptosis in vitro. Toll-like-Receptor 3 (TLR3) is an important innate immune receptor responsible for the initial recognition of ZIKV. ZIKV depletes NS/PCs through TLR3 activation, and impedes neuronal differentiation in a cell-strain-dependent manner, which is well correlated with the upregulation of the innate immune genes transcription profile. Although significant progresses have been made in the past years, it remains largely unknown how ZIKV transports from the mother to the fetal brain, and how ZIKV targets NS/PCs to cause neurogenesis reduction. In this project, I developed a mouse model to explore the role of microglia in ZIKV dissemination to the fetal brain, and used human NS/PC (hNS/PC) lines to determine the role of innate immune genes in neurogenesis reduction after ZIKV infection. In this dissertation, I will briefly discuss ZIKV and the innate immunity in ZIKV infection. Next, I will describe my findings that show 1) YS-derived microglial progenitors can act as “Trojan horses” to bring ZIKV from the mother to the fetal brain in a restricted time window, ablation of microglial progenitors reduced the viral load in embryonic mouse brains; and 2) ZIKV infects NS/PCs and overactivates innate immune responses to inhibit neurogenesis, whereas experimentally inhibiting the overactivated innate immune responses ameliorates neurogenesis deficits. Finally, I will summarize and discuss the data integrating the role of innate immunity in ZIKV infection and neurogenesis abnormalities.

Biology, Neuroscience, Biology, Virology, Biology, Cell