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Genome-Wide Rnai Screen Identifies Broadly-Acting Host Factors That Inhibit Arbovirus Infection." Plos Pathogens.10,2

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Genome-Wide Rnai Screen Identifies Broadly-Acting Host Factors That Inhibit Arbovirus Infection. View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Digital Commons@Becker Washington University School of Medicine Digital Commons@Becker Open Access Publications 2014 Genome-wide RNAi screen identifies broadly- acting host factors that inhibit arbovirus infection Ari Yasunaga University of Pennsylvania Sheri L. Hanna University of Pennsylvania Jianqing Li Washington University School of Medicine in St. Louis Hyelim Cho Washington University School of Medicine in St. Louis Patrick P. Rose University of Pennsylvania See next page for additional authors Follow this and additional works at: http://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Yasunaga, Ari; Hanna, Sheri L.; Li, Jianqing; Cho, Hyelim; Rose, Patrick P.; Spiridigliozzi, Anna; Gold, Beth; Diamond, Michael S.; and Cherry, Sara, ,"Genome-wide RNAi screen identifies broadly-acting host factors that inhibit arbovirus infection." PLoS Pathogens.10,2. e1003914. (2014). http://digitalcommons.wustl.edu/open_access_pubs/2700 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Ari Yasunaga, Sheri L. Hanna, Jianqing Li, Hyelim Cho, Patrick P. Rose, Anna Spiridigliozzi, Beth Gold, Michael S. Diamond, and Sara Cherry This open access publication is available at Digital Commons@Becker: http://digitalcommons.wustl.edu/open_access_pubs/2700 Genome-Wide RNAi Screen Identifies Broadly-Acting Host Factors That Inhibit Arbovirus Infection Ari Yasunaga1,2, Sheri L. Hanna1,2, Jianqing Li3, Hyelim Cho3, Patrick P. Rose1,2, Anna Spiridigliozzi1,2, Beth Gold1,2, Michael S. Diamond3, Sara Cherry1,2* 1 Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 2 Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 3 Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America Abstract Vector-borne viruses are an important class of emerging and re-emerging pathogens; thus, an improved understanding of the cellular factors that modulate infection in their respective vertebrate and insect hosts may aid control efforts. In particular, cell- intrinsic antiviral pathways restrict vector-borne viruses including the type I interferon response in vertebrates and the RNA interference (RNAi) pathway in insects. However, it is likely that additional cell-intrinsic mechanisms exist to limit these viruses. Since insects rely on innate immune mechanisms to inhibit virus infections, we used Drosophila as a model insect to identify cellular factors that restrict West Nile virus (WNV), a flavivirus with a broad and expanding geographical host range. Our genome-wide RNAi screen identified 50 genes that inhibited WNV infection. Further screening revealed that 17 of these genes were antiviral against additional flaviviruses, and seven of these were antiviral against other vector-borne viruses, expanding our knowledge of invertebrate cell-intrinsic immunity. Investigation of two newly identified factors that restrict diverse viruses, dXPO1 and dRUVBL1, in the Tip60 complex, demonstrated they contributed to antiviral defense at the organismal level in adult flies, in mosquito cells, and in mammalian cells. These data suggest the existence of broadly acting and functionally conserved antiviral genes and pathways that restrict virus infections in evolutionarily divergent hosts. Citation: Yasunaga A, Hanna SL, Li J, Cho H, Rose PP, et al. (2014) Genome-Wide RNAi Screen Identifies Broadly-Acting Host Factors That Inhibit Arbovirus Infection. PLoS Pathog 10(2): e1003914. doi:10.1371/journal.ppat.1003914 Editor: Abraham L. Brass, Massachusetts General Hospital, United States of America Received April 22, 2013; Accepted December 18, 2013; Published February 13, 2014 Copyright: ß 2014 Yasunaga et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: SC is a recipient of the Burroughs Wellcome Investigators in the Pathogenesis of Infectious Disease Award. This work was supported by grants from the National Institutes of Health R01AI074951, U54AI057168, R21AI103441, and RO1AI095500 to SC, R01AI104972 to MSD, and F32AI80111 to SH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] Introduction viruses (JEV) [6]. DENV is endemic in more than 110 countries with 3.6 billion people at risk, and 390 million people infected yearly Historically, West Nile virus (WNV) epidemics were observed in [7,8]. At present, there are no specific antiviral therapies against any Africa, the Middle East, Europe, India, Australia, and parts of Asia, flavivirus, and only three insect-borne flaviviruses have approved In 1999, WNV entered into the North America as part of an vaccines for humans (YFV, TBEV, and JEV) [9]. outbreak of neuroinvasive disease in New York City [1], and since Flaviviruses are small (,50 nm diameter) enveloped viruses that then has become endemic in the United States with large numbers of contain a single-stranded, positive-sense RNA genome of ,11-kb cases occurring annually in different regions of the country. Indeed, with a 59 cap, but unlike mRNA, lack a 39 polyadenylated tail the occurrence, size, and severity of outbreaks in humans overall [10]. WNV enters both vertebrate and invertebrate cells through have increased worldwide since the mid 1990s [2], with a large clathrin-mediated endocytosis [11], and then traffics to an acidic outbreak in Texas in 2012 leading to many fatalities [3,4]. Different compartment that facilitates viral fusion with endosomal mem- strains of WNV, with variable worldwide distributions, exhibit branes and release of the nucleocapsid into the cytoplasm [12]. significant differences in pathogenesis. In humans infected with The viral genome encodes one open reading frame and is North American WNV strains, approximately 80% of infections are translated as a single polyprotein at the rough endoplasmic asymptomatic, with 20% developing WNV fever and other relatively reticulum (ER), which is subsequently processed by both viral and mild symptoms, and 1% progressing to encephalitis, meningitis, or cellular proteases into 3 structural and 7 non-structural viral flaccid paralysis [2]. In contrast, WNV-Kunjin, endemic in proteins [13]. Viral RNA replication occurs within cytoplasmic Australia, has not been associated with any human fatalities or complexes associated with perinuclear membranes requiring lipid severe disease [5]. The natural transmission cycle of WNV is rearrangements [14,15,16,17], and progeny viruses bud into the between mosquitoes and birds, with humans, horses, and other ER and traffic through the Golgi network where virions are vertebrates being incidental dead-end hosts [2]. WNV is a member processed into mature particles prior to exocytosis [18]. of the Flavivirus genus, which includes many globally important While there has been extensive study into the cellular pathways vector-borne pathogens, such as Dengue (DENV), yellow fever that are hijacked to facilitate WNV infection in mammalian cells, (YFV), tick-borne encephalitis (TBEV), and Japanese encephalitis less is known about the cell-intrinsic pathways that restrict WNV PLOS Pathogens | www.plospathogens.org 1 February 2014 | Volume 10 | Issue 2 | e1003914 Broadly-Acting Anti-Arboviral Host Factors Author Summary flaviviral in genome-wide RNAi screens [24,32], only 2 of these are conserved between humans and insects. We optimized the West Nile virus (WNV) is an insect-borne virus that has re- assay for the discovery of restriction factors and identified 50 genes emerged globally and for which there are no specific that when silenced resulted in enhanced WNV infection in therapeutics or vaccines. We set out to identify cellular Drosophila cells. All 50 are conserved in mosquitoes and 86% have factors that impact infection using Drosophila as a model clearly defined human orthologs. Furthermore, 17 of these genes insect. Using a genome-wide RNAi screen we identified a had antiviral activity against multiple flaviviruses, and 7 genes large number of genes that altered WNV infection. We were antiviral against a diverse panel of additional vector-borne focused on genes that restricted infection and validated 50 RNA viruses. We focused on two broadly acting conserved genes, genes that were conserved from insects to humans that dRUVBL1 (pontin) and dXPO1 (embargoed), and found both inhibited infection. Since WNV is a flavivirus, we tested restricted viral infection in adult flies, were antiviral in mosquito whether additional flaviviruses were restricted by these Aedes aegypti cell culture as well as in human cells. Furthermore, genes and found that 17 also had antiviral activity against Dengue virus. There are additional families of insect- since WNV is neurotropic we tested whether RUVBL1 contrib- transmitted viruses that infect humans.
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