Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication

Sun, Xiaoming; Hua, Stéphane; Chen, Hsiao-Rong; Ouyang, Zhengyu; Einkauf, Kevin; Tse, Samantha; Ard, Kevin L.; Ciaranello, Andrea; Yawetz, Sigal; Sax, Paul E.; Rosenberg, Eric S.; Lichterfeld, Mathias; Yu, Xu G.

doi:10.1016/j.celrep.2017.11.087

Cited by 71 publications

(82 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Host-virus interaction and its effect on host physiology has so far remained mostly unexplored. Recently, studies based on transcriptomic and proteomic analyses have been instrumental in advancing our understanding of how viruses can affect host physiology (Merkling et al, 2015;Sun et al, 2017;Dong et al, 2017). Our results further emphasize the applicability of such transcriptomic analyses in understanding host-virus interactions and their molecular regulators.…”

Section: Discussionsupporting

confidence: 57%

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

Harsh

Kenney

et al. 2020

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 57%

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

Harsh

Kenney

et al. 2020

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…and interferon-inducible transmembrane proteins (IFITM) family members act as inhibitory factors (Savidis et al, 2016a,b;Meertens et al, 2017;Sun et al, 2017;Van der Hoek et al, 2017;Soto-Acosta et al, 2018). In this study, we identified HCAR2, a G protein-coupled receptor which expression is induced by ZIKV, functions as a restriction factor for ZIKV replication.…”

Section: Discussionmentioning

confidence: 76%

Hydroxycarboxylic Acid Receptor 2 Is a Zika Virus Restriction Factor That Can Be Induced by Zika Virus Infection Through the IRE1-XBP1 Pathway

Luo

Zhou

et al. 2020

Front. Cell. Infect. Microbiol.

View full text Add to dashboard Cite

Zika virus (ZIKV) is an emerging arthropod-borne virus and belongs to the Flaviviridae family. The infection of ZIKV has become the global health crisis because of its rapid spread and association with severe neurological disorders, including congenital microcephaly and Guillain-Barre Syndrome. To identify host factors contributing to ZIKV pathogenesis, transcriptomic landscape in ZIKV-infected cells was examined with mRNA microarray analysis and we observed that the expression of hydroxycarboxylic acid receptor 2 (HCAR2) could be significantly induced by ZIKV infection. By utilizing two IRE1 inhibitors and XBP1-specific shRNAs, we revealed that the up-regulation of HCAR2 expression induced by ZIKV was dependent on the IRE1-XBP1 pathway. Through the CRISPR/Cas9 system, we generated HCAR2-deficient cell clones in two cell types (human lung carcinoma epithelial A549 cell and human hepatoma Huh7.5 cell). We found that the depletion of HCAR2 significantly increased the replication level of ZIKV, including RNA levels, protein expression levels, and viral titers. In addition, our data demonstrated that the antiviral effect of HCAR2 was not involved in viral entry process and was not dependent on its antilipolytic effect on nicotinic acid/HCAR2-mediated signaling pathway. Taken together, our results indicated that HCAR2 could function as a restriction factor in control of ZIKV replication, potentially providing a novel molecular target for anti-ZIKV therapeutics.

show abstract

“…Dendritic cells are critical cells which bridge virus detection to activation of antiviral host immunity during natural infection or vaccination. Many viruses, however, have evolved to overcome DC responses; for example, ZIKV infects human DCs and does not cause their activation (64)(65)(66). We explored such ZIKV-DC interactions as a model to define whether increasing of CpG dinucleotides in the RNA viral genome may serve as an approach to subvert impaired antiviral responses in DCs.…”

Section: Immunogenicity and Protective Efficacy Of Cpg-recoded Zikv Vmentioning

confidence: 99%

CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

et al. 2020

View full text Add to dashboard Cite

Experimental increase of CpG dinucleotides in an RNA virus genome impairs infection providing a promising approach for vaccine development. While CpG recoding is an emerging and promising vaccine approach, little is known about infection phenotypes caused by recoded viruses in vivo. For example, infection phenotypes, immunogenicity, and protective efficacy induced by CpG-recoded viruses in different age groups were not studied yet. This is important, because attenuation of infection phenotypes caused by recoded viruses may depend on the population-based expression of cellular components targeting viral CpG dinucleotides. In the present study, we generated several Zika virus (ZIKV) variants with the increasing CpG content and compared infection in neonatal and adult mice. Increasing the CpG content caused host-age-dependent attenuation of infection with considerable attenuation in neonates and high attenuation in adults. Expression of the zinc-finger antiviral protein (ZAP)-the host protein targeting viral CpG dinucleotides-was also age-dependent. Similar to the wild-type virus, ZIKV variants with the increased CpG content evoked robust cellular and humoral immune responses and protection against lethal challenge. Collectively, the host age should be accounted for in future studies on mechanisms targeting viral CpG dinucleotides, development of safe dinucleotide recoding strategies, and applications of CpG-recoded vaccines.

show abstract

Transcriptional Changes during Naturally Acquired Zika Virus Infection Render Dendritic Cells Highly Conducive to Viral Replication

Cited by 71 publications

References 50 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

Hydroxycarboxylic Acid Receptor 2 Is a Zika Virus Restriction Factor That Can Be Induced by Zika Virus Infection Through the IRE1-XBP1 Pathway

CpG-Recoding in Zika Virus Genome Causes Host-Age-Dependent Attenuation of Infection With Protection Against Lethal Heterologous Challenge in Mice

Contact Info

Product

Resources

About