The Zika Virus Capsid Disrupts Corticogenesis by Suppressing Dicer Activity and miRNA Biogenesis

Abstract

Highlights d Defining the ZIKV-host interactome in NSCs identifies a capsid-Dicer interaction d Capsid from ZIKV but not other flaviviruses binds Dicer and blocks its activity d ZIKV capsid dampens global miRNA production in NSCs by targeting Dicer d ZIKV capsid is necessary and sufficient to drive neurodevelopmental defects

Functional Mapping of AGO-Associated Zika Virus-Derived Small Interfering RNAs in Neural Stem Cells

“…ZIKV strain SPH2015 and according ZIKV-H41R mutant virus were separately rescued from the ZIKV infection clone as described previously ( Zeng et al., 2020 ). Vero cells were cultured in DMEM with 10% FBS and 4 mM glutamine.…”

“…NSCs were plated on poly-L-Ornithine (10 µg/ml) coated plates when adherent culture was needed. ZIKV WT capsid and H41R capsid were cloned into lentivirus pCDH-cmv-mcs-ef1-puro vector as described previously ( Zeng et al., 2020 ). Lentiviruses were generated by co-transfection of pCDH-vector, pCDH-Flag-capsid WT or pCDH-Flag-capsid H41R with three packaging plasmids into HEK293T cells.…”

“…ZIKV has an intrinsic tropism for neural stem and progenitor cells (NSCs) in cell cultures, brain organoids and fetal brain slices ( Cugola et al., 2016 ; Dang et al., 2016 ; Garcez et al., 2016 ; Liang et al., 2016 ; Qian et al., 2016 ; Tang et al., 2016 ), whereas ZIKV has much lower infectivity to more differentiated immature or mature neurons ( Li et al., 2016a ; Muffat et al., 2018 ). ZIKV infection impairs NSC proliferation and differentiation, triggers cell death, and results in cerebral developmental delay ( Shao et al., 2016 ; Shao et al., 2017 ; Nielsen-Saines et al., 2019 ; Zeng et al., 2020 ). Notably, mammalian multipotent stem cells, including NSCs, intrinsically produce little interferon (IFN) and response poorly to IFN treatment compare to somatic cells ( Hong and Carmichael, 2013 ; Wu et al., 2019 ), and thus these cells often rely on other machineries once the virus breaches the surveillance ( Ding and Voinnet, 2007 ).…”

“…Accordingly, we defined the capsid H41R mutation from histidine to arginine (R), which on longer suppresses Dicer enzymatic activity due to the loss of interaction with Dicer. As a result, the ZIKV-H41R mutant virus failed to dampen miRNA biogenesis in NSCs, nor impaired corticogenesis in vivo ( Zeng et al., 2020 ). However, whether ZIKV also utilizes its capsid to dampen Dicer-dependent viRNA production remains unknown.…”

ZIKV viral proteins and their roles in virus-host interactions

“…No significant difference between viral strains of Asian and African lineages was shown for the interaction between C protein and the NMD pathway (Fontaine et al, 2018). Recently, a study also reported that C protein specifically binds and inhibits Dicer to limit host miRNA biogenesis in neural stem cells (NSCs), resulting in neurodevelopmental defects and virus immune evasion (Zeng et al, 2020).…”