Zika virus non-structural protein NS4A restricts eye growth in
Dis Model Mech
P30 CA091842/CA/NCI NIH HHS/United States
R01 AI110675/AI/NIAID NIH HHS/United States
UL1 TR000448/TR/NCATS NIH HHS/United States
Drosophila; Eye development; Jak/Stat; Pathogenesis; Zika virus.
To gain a comprehensive view of the changes in host gene expression underlying Zika virus (ZIKV) pathogenesis, we performed whole-genome mRNAseq of ZIKV infected Drosophila adult flies. RNA-seq analysis revealed that ZIKV infection alters several and diverse biological processes including stress, locomotion, lipid metabolism, imaginal disc morphogenesis and regulation of JAK/STAT signaling, To explore the interaction between ZIKV infection and JAK/STAT signaling regulation, we generated genetic constructs overexpressing ZIKV-specific non-structural proteins NS2A, NS2B, NS4A and NS4B. We find that ectopic expression of non-structural proteins in the developing Drosophila eye significantly restricts growth of the larval and adult eye and correlates with a considerable repression of the in vivo JAK/STAT reporter, 10XStat92E-GFP At the cellular level, eye growth defects are associated with reduced rate of proliferation without affecting the overall rate of apoptosis. In addition, ZIKV NS4A genetically interacts with the JAK/STAT signaling components; co-expression of NS4A along with dominant negative form of domeless or StatRNAi results in aggravated reduction in eye size while co-expression of NS4A in HopTuml mutant background partially rescues the Hop-induced eye overgrowth phenotype. The function of ZIKV NS4A in regulating growth is maintained in the wing, where ZIKV NS4A overexpression in the pouch domain results in reduced growth linked with diminished expression of Notch targets, Wingless and Cut and the Notch reporter, NRE-GFP Thus, our study provides evidence that ZIKV infection in Drosophila results in restricted growth of the developing eye and wing, wherein eye phenotype is induced through regulation of JAK/STAT signaling while restricted wing growth is through regulation of Notch signaling. The interaction of ZIKV non-structural proteins with the conserved host signaling pathways further advance our understanding of ZIKV-induced pathogenesis.
Harsh, S., Fu, Y., Kenney, E., Han, Z., & Eleftherianos, I. (2020). Zika virus non-structural protein NS4A restricts eye growth in. Dis Model Mech, (). http://dx.doi.org/10.1242/dmm.040816