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

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Dicer-2 Regulates Resistance and Maintains Homeostasis Against Zika Virus Infection in Drosophila Dicer-2 Regulates Resistance and Maintains Homeostasis against Zika Virus Infection in Drosophila This information is current as Sneh Harsh, Yaprak Ozakman, Shannon M. Kitchen, of September 30, 2021. Dominic Paquin-Proulx, Douglas F. Nixon and Ioannis Eleftherianos J Immunol published online 10 October 2018 http://www.jimmunol.org/content/early/2018/10/09/jimmun ol.1800597 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2018/10/10/jimmunol.180059 Material 7.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 30, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 10, 2018, doi:10.4049/jimmunol.1800597 The Journal of Immunology Dicer-2 Regulates Resistance and Maintains Homeostasis against Zika Virus Infection in Drosophila Sneh Harsh,* Yaprak Ozakman,* Shannon M. Kitchen,† Dominic Paquin-Proulx,†,1 Douglas F. Nixon,† and Ioannis Eleftherianos* Zika virus (ZIKV) outbreaks pose a massive public health threat in several countries. We have developed an in vivo model to investigate the host–ZIKV interaction in Drosophila. We have found that a strain of ZIKV replicates in wild-type flies without reducing their survival ability. We have shown that ZIKV infection triggers RNA interference and that mutating Dicer-2 results in enhanced ZIKV load and increased susceptibility to ZIKV infection. Using a flavivirus-specific Ab, we have found that ZIKV is localized in the gut and fat body cells of the infected wild-type flies and results in their perturbed homeostasis. In addition, Dicer-2 mutants display severely reduced insulin activity, which could contribute toward the increased mortality of these flies. Our work establishes the suitability of Drosophila as the model system to study host–ZIKV dynamics, which is expected to greatly advance Downloaded from our understanding of the molecular and physiological processes that determine the outcome of this disease. The Journal of Immunology, 2018, 201: 000–000. ika virus (ZIKV) is a hitherto understudied member of the effect of ZIKV infection on the immune signaling and func- Flaviviridae, a viral family that also includes yellow fe- tion of animal models will be particularly insightful because it Z ver, West Nile virus (WNV), and dengue virus (DENV) could potentially lead to the identification of anti-ZIKV im- http://www.jimmunol.org/ (1). In recent years, because of the wide geographical distribu- mune mechanisms in humans. tion of the mosquito vector, ZIKV suddenly expanded its range The use of the fruit fly Drosophila melanogaster has led to sig- dramatically, and severe outbreaks appeared in the Americas and nificant advances in the characterization of the molecular events other parts of the world (2). Being a vector-borne virus, ZIKV- leading to the activation of immune responses against infectious induced outbreaks are difficult to control. As vector control is the microorganisms, including viral pathogens (4, 5). Apart from those only viable alternative for alleviating the disease, a thorough viruses that naturally infect Drosophila (6), previous work indicates understanding of host–ZIKV interaction is critical. Thus, there is that the fly is also a suitable model for dissecting host interactions an urgent need to develop an in vivo model for identifying and with human pathogenic viruses including ZIKV (7, 8). Drosophila, by guest on September 30, 2021 characterizing the number and types of molecular components for instance, was instrumental in deciphering antiviral immune that directly or indirectly participate in the host immune re- mechanisms against Sindbis virus (SINV), vesicular stomatitis virus sponse against ZIKV. Because host innate immune responses are (VSV), and WNV and, in particular, the importance of RNA inter- evolutionary conserved across many phyla (3), investigating the ference (RNAi) against these viruses (9–11). Apart from unraveling the cellular and molecular basis of antiviral immunity, Drosophila is *Department of Biological Sciences, The Institute for Biomedical Sciences, The also a suitable model for understanding host–virus interaction and † George Washington University, Washington, DC 20052; and Department of Micro- the associated pathology (12, 13). Few compelling evidences further biology, Immunology, and Tropical Medicine, GW School of Medicine & Health Sciences, The George Washington University, Washington, DC 20052 indicate that Drosophila can be a reliable model to analyze virus 1Current address: U.S. Military HIV Research Program/Henry M. Jackson Founda- tropism (14). The insect-specific viruses Drosophila C virus (DCV) tion, Bethesda, MD. and Flock House virus (FHV), for example, have been shown to ORCIDs: 0000-0002-1177-8825 (S.M.K.); 0000-0003-1407-3414 (D.P.-P.); 0000- infect the fat body, digestive tract, trachea, and egg chamber, which 0002-2801-1786 (D.F.N.). results in infection-induced pathologies (12, 15, 16). These findings Received for publication April 25, 2018. Accepted for publication September 17, are of paramount importance to elucidate the physiological mech- 2018. anisms that regulate the complex interactions between insects and This work was supported by an administrative supplement through Grant viral pathogens. Comparative genomics studies have addressed the R01AI110675 from the National Institute of Allergy and Infectious Diseases and by funds through The George Washington University SMHS IMP program conservation between Drosophila and mosquitoes and shown that (to D.F.N.). Drosophila developmental genes are largely conserved in three Address correspondence and reprint requests to Prof. Ioannis Eleftherianos, Depart- vector mosquito species (17). Deciphering the complete genome ment of Biological Sciences, The George Washington University, Science and Engi- neering Hall, 800 22nd Street NW, Washington, DC 20052. E-mail address: sequences of the mosquito vectors Anopheles gambiae and A. [email protected] aegypti has enabled the identification and comparison of antiviral The online version of this article contains supplemental material. immune genes like Dicer-2 and Ago-2 (18–20). In the context of Abbreviations used in this article: DCV, Drosophila C virus; DENV, dengue virus; host pathology, forward genetic screens in Drosophila have identi- dpi, day postinjection; DXV, Drosophila X virus; EE, enteroendocrine cell; FHV, fied genes regulating Plasmodium growth in A. gambiae (21). Flock House virus; Imd, immune deficiency; ISC, intestinal stem cell; LD, lipid droplet; miRNA, microRNA; PH3, phospho-histone 3; piRNA, Piwi-interacting Therefore, molecular and functional characterization of innate im- RNA; qRT-PCR, quantitative RT-PCR; RISC, RNA-induced silencing complex; mune factors acting against ZIKVand the consequent ZIKV-induced RNAi, RNA interference; SINV, Sindbis virus; siRNA, small interfering RNA; Tot, pathogenesis will potentially lead to a comprehensive understanding Turandot; VSV, vesicular stomatitis virus; WNV, West Nile virus; ZIKV, Zika virus. of the host–ZIKV interactions, which in turn will potentially lead to Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 novel strategies for blocking ZIKV transmission. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1800597 2 ZIKA VIRUS INFECTION AND INNATE IMMUNITY IN DROSOPHILA In the absence of a classical adaptive immune system, Drosophila After 3 h, the inoculum was removed, and cells were overlaid with semi- relies on innate defenses for immunity against viral infections. For solid medium containing 1% carboxymethyl cellulose (Sigma-Aldrich). instance, the Toll, immune deficiency (Imd), and JAK/STAT Cells were further incubated for 5 d, fixed with 4% paraformaldehyde (Electron Microscopy Sciences), and stained with 0.5% aqueous crystal vi- signaling pathways in Drosophila participate in antiviral re- olet solution (Sigma-Aldrich) for plaque visualization. Titers were expressed sponses; however, each of those pathways confers antiviral ef- as PFU per milliliter. fects against certain viruses (22–24). The central antiviral immune response in the fly involves the RNAi mechanism, a Fly infection conserved sequence-specific nucleic acid–based immune defense To avoid heterogeneity in ZIKV load, only adult female flies were used in that is induced by dsRNA. In Drosophila, RNAi involves the RNase these experiments. Injections were performed by anesthetizing the flies with Dicer-2 that recognizes and cleaves dsRNA to generate viral small CO2. For each experiment, 2–5-d-old adult female flies were injected with ZIKV suspensions in PBS (pH 7.5) using a nanoinjector (Nanoject III; interfering RNAs (siRNAs) (25, 26). These siRNAs are loaded onto Drummond Scientific). ZIKV stocks were prepared in PBS (pH 7.5). Heat- Argonaute-2
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