Abstract
ABSTRACTTo gain a comprehensive view of the changes in host gene expression underlying Zika virus (ZIKV) pathogenesis, we performed whole-genome RNA sequencing (RNA-seq) 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 found that ectopic expression of non-structural proteins in the developing Drosophila eye significantly restricts growth of the larval and adult eye and correlates with 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 the dominant-negative form of domeless or StatRNAi results in aggravated reduction in eye size, while co-expression of NS4A in HopTuml (also known as hopTum) 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 (Wg) 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, whereas restricted wing growth is induced 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.This article has an associated First Person interview with the first author of the paper.
Highlights
Zika virus (ZIKV) is an emerging pathogen of substantial public health concern, and belongs to the flavivirus family that includes dengue, West Nile and yellow fever viruses
Knockdown of Stat along with NS4A overexpression leads to synergistic reduction in eye size, while NS4A overexpression rescues Hop-mediated eye overgrowth After validating the status of JAK/STAT signaling in the developing eye tissue carrying overexpression of ZIKV NS4A protein, we investigated the genetic interaction of ZIKV NS4A with the regulators of JAK/STAT signaling
We have shown that infection of adult Drosophila with the MR766 strain of ZIKV results in differential expression of genes implicated in crucial biological processes
Summary
Zika virus (ZIKV) is an emerging pathogen of substantial public health concern, and belongs to the flavivirus family that includes dengue, West Nile and yellow fever viruses. ZIKV can infect the eye, resulting in conjunctivitis in up to 15% of the patients (Sun et al, 2016; Miner et al, 2016; Furtado et al, 2016). ZIKV is primarily transmitted by mosquitos, perinatal and congenital infections, infection through blood transfusion as well as sexual transmission have been reported (Musso et al, 2014; Mead et al, 2018; Foy et al, 2011). It is the correlation of ZIKV-associated outbreak with microcephaly that makes ZIKA infection even more serious (Li et al, 2016a). No drug or vaccine is available to prevent or treat ZIKV infection (Fauci and Morens, 2016)
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