title: Genome-wide RNAi screen identifies broadly-acting host factors that inhibit arbovirus infection.
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.
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America ; Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Ari
authors.initials: A
authors.lastname: Yasunaga
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America ; Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Sheri L
authors.initials: SL
authors.lastname: Hanna
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Jianqing
authors.initials: J
authors.lastname: Li
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Hyelim
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America ; Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Patrick P
authors.initials: PP
authors.lastname: Rose
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America ; Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Anna
authors.initials: A
authors.lastname: Spiridigliozzi
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America ; Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Beth
authors.initials: B
authors.lastname: Gold
authors.affiliation: Departments of Medicine, Molecular Microbiology, Pathology & Immunology, Washington University School of Medicine, St Louis, Missouri, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.affiliation: Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America ; Penn Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Cherry
mesh_terms: D000818:Animals; D009033:Culicidae; D004265:DNA Helicases / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster; D005416:Flavivirus / Q000235:genetics; D018177:Flavivirus Infections / Q000235:genetics* / Q000276:immunology; D055106:Genome-Wide Association Study; D006790:Host-Parasite Interactions / Q000235:genetics*; D006801:Humans; D028884:Karyopherins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000032:analysis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014902:West Nile virus / Q000235:genetics / Q000276:immunology; D000097606:Exportin 1 Protein
chemical_list: D004265:DNA Helicases; D029721:Drosophila Proteins; D028884:Karyopherins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C504804:pont protein, Drosophila