Dicer-2 Regulates Resistance and Maintains Homeostasis against Zika Virus Infection in <i>Drosophila</i>

Harsh, Sneh; Ozakman, Yaprak; Kitchen, Shannon M.; Paquin‐Proulx, Dominic; Nixon, Douglas F.; Eleftherianos, Ioannis

doi:10.4049/jimmunol.1800597

Cited by 39 publications

(64 citation statements)

References 127 publications

(186 reference statements)

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“…We generated complete transcriptomes from Drosophila wild-type female adult flies infected with the MR766 strain of ZIKV (Harsh et al, 2018;Liu et al, 2018) or injected with PBS (negative/sterile control) (Harsh et al, 2018). We examined gene transcript levels at two timepoints, 4 and 8 days post-injection (dpi) (Fig.…”

Section: Zikv Infection Induces Distinct Transcriptomic Profiles In Dmentioning

confidence: 99%

“…1A). The timepoints were chosen based on the ZIKV load, where 4 dpi corresponds to the early stage of infection, while 8 dpi corresponds to the stage when the infection reaches peak titers (Harsh et al, 2018). The numbers of sequence reads mapped to 96.37% of the D. melanogaster genome ( Fig.…”

Section: Zikv Infection Induces Distinct Transcriptomic Profiles In Dmentioning

confidence: 99%

“…Overexpression of human cytomegalovirus immediate-early genes in Drosophila embryos results in abnormal embryonic development associated with disrupted adherens junctions (Steinberg et al, 2008). Recently, there have also been efforts to dissect host-ZIKV interactions using Drosophila as the model organism (Harsh et al, 2018;Link et al, 2019;Liu et al, 2018). Findings from these studies indicate that Drosophila can be a reliable model to analyze ZIKV tropism.…”

Section: Introductionmentioning

confidence: 99%

“…Findings from these studies indicate that Drosophila can be a reliable model to analyze ZIKV tropism. ZIKV was shown to replicate in the fat body, midgut, crop and brain of the infected adult fly, and result in perturbation in lipid metabolism, intestinal homeostasis and autophagy Harsh et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Zika virus non-structural protein NS4A restricts eye growth inDrosophilathrough regulation of JAK/STAT signaling

Harsh

Kenney

et al. 2020

Disease Models &Amp; Mechanisms

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To 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 ZIKVspecific 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 hop Tum ) 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.

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Section: Zikv Infection Induces Distinct Transcriptomic Profiles In Dmentioning

confidence: 99%

Section: Zikv Infection Induces Distinct Transcriptomic Profiles In Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Zika virus non-structural protein NS4A restricts eye growth inDrosophilathrough regulation of JAK/STAT signaling

Harsh

Kenney

et al. 2020

Disease Models &Amp; Mechanisms

Self Cite

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“…Drosophila has been developed as a model of viral infection (Harsh et al, 2018;Liu et al, 2018), and we recently showed that expression of the Zika protein NS4A results in reduced brain size in Drosophila. Strikingly, NS4A expression in Ankle2 A /+ heterozygous animals leads to a more severe phenotype than NS4A expression in a wild type background, and these animals display brain phenotypes that mimic Ankle2 CRIMIC null mutants (Shah et al, 2018).…”

Section: Ns4a Targets the Ankle2 Pathwaymentioning

confidence: 99%

Ankle2, A Target of Zika Virus, Controls Asymmetric Cell Division of Neuroblasts and Uncovers a Novel Microcephaly Pathway

Link

Chung

Jolly

et al. 2019

Preprint

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words)Neuroblasts in flies divide asymmetrically by establishing polarity, distributing cell fate determinants asymmetrically, and positioning their spindle for cell division. The apical complex contains aPKC, Bazooka (Par3), and Par6, and its activity depends on L(2)gl. We show that Ankle2 interacts with L(2)gl and affects aPKC. Reducing Ankle2 levels disrupts ER and nuclear envelope morphology, releasing the kinase Ballchen/VRK1 into the cytosol. These defects are associated with reduced phosphorylation of aPKC, disruption of Par complex localization, and spindle alignment defects. Importantly, removal of one copy of ballchen/VRK1 or l(2)gl suppresses the loss of Ankle2 and restores viability and brain size. The Zika virus NS4A protein 3 interacts with Drosophila Ankle2 and VRK1 in dividing neuroblasts. Human mutational studies implicate this neural cell division pathway in microcephaly and motor neuron disease. In summary, NS4A, ANKLE2, VRK1 and LLGL1 define a novel pathway that impinges on asymmetric determinants of neural stem cell division.However, all experiments in worms were performed at the embryonic two-cell stage, and no other phenotypes were reported except early lethality. Whilst mutations in ANKLE2 have been associated with severe microcephaly (OFC z-sore = -2.5 to -9), human VRK1 pathogenic variant alleles can cause a neurological disease trait consisting of complex motor and sensory axonal neuropathy and microcephaly .Mutations in both Ankle2 and the fly homologue of VRK1, ballchen, cause a loss of neuroblasts in 3 rd instar larval brains in Drosophila (Yamamoto et al., 2014;Yakulov et al., 2014). Neuroblasts (NBs) divide asymmetrically and are often used as a model to investigate stem cell biology (Homem and Knoblich, 2012) and asymmetric cell division (Gallaud et al., 2017). Most NBs in the larval central brain give rise to another NB and a smaller ganglion mother cell (GMC), which then divides once again to produce neurons or glia. Proper NB maintenance and regulation is essential for precise development of the adult nervous system, and misregulation of NB number or function can lead to defects in brain size (Wang et al., 2009;Gateff and Schneiderman, 1974).Congenital Zika infection in humans during pregnancy has been associated with severe microcephaly that can be as dramatic as certain genetic forms of microcephaly including phenotypes associated with bi-allelic mutations in MCPH16/ANKLE2 (Moore et al., 2017;Yamamoto et al., 2014). Recently, we showed that a Zika protein, NS4A, physically interacts with ANKLE2 in human cells. Expression of NS4A in larval brains causes microcephaly, induces apoptosis, and reduces proliferation. Importantly, expression of human ANKLE2 in flies that express NS4A suppresses the associated phenotypes, demonstrating that NS4A interacts with the ANKLE2 protein and inhibits its function (Shah et al., 2018). Interestingly, the Zika virus crosses the blood brain barrier and targets radial glial cells, the neural progenitors in the vertebrate cortex (Devhare et al., 20...

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Functional analysis of Dicer‐2 gene in Bombyx mori resistance to BmNPV virus

Xia

et al. 2020

Arch Insect Biochem Physiol

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Bombyx mori nucleopolyhedrovirus (BmNPV) is a primary pathogen in silkworm, and the molecular mechanism of B. mori defense to BmNPV infection is still unclear. RNA interference (RNAi) is well‐known as an intracellular conserved mechanism that is critical in gene regulation and cell defense. The antiviral RNAi pathway processes viral double‐stranded RNA (dsRNA) into viral small interfering RNAs that guide the recognition and cleavage of complementary viral target RNAs. In this study, a Dicer‐2 (Dcr2) gene was identified in B. mori and its antiviral function was explored. Dcr2 messenger RNA (mRNA) expression was the highest in hemocytes and expressed in all stages of silkworm growth. After infection with BmNPV, the expression of Dcr2 mRNA was significantly increased after infection in midgut and hemocytes. The expression of Dcr2 was significantly upregulated by injecting dsRNA (dsBmSPH‐1) into silkworm after 48 hr. Knocking down the expression level of Dcr2 using specific dsRNA in silkworm, which modestly enhanced the production of viral genomic DNA. Our results suggested that the Dcr2 gene in B. mori plays an important role in against BmNPV invasion.

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Dicer-2 Regulates Resistance and Maintains Homeostasis against Zika Virus Infection in Drosophila

Cited by 39 publications

References 127 publications

Zika virus non-structural protein NS4A restricts eye growth inDrosophilathrough regulation of JAK/STAT signaling

Zika virus non-structural protein NS4A restricts eye growth inDrosophilathrough regulation of JAK/STAT signaling

Ankle2, A Target of Zika Virus, Controls Asymmetric Cell Division of Neuroblasts and Uncovers a Novel Microcephaly Pathway

Functional analysis of Dicer‐2 gene in Bombyx mori resistance to BmNPV virus

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