title: Novel Drosophila viruses encode host-specific suppressors of RNAi.
abstract: The ongoing conflict between viruses and their hosts can drive the co-evolution between host immune genes and viral suppressors of immunity. It has been suggested that an evolutionary 'arms race' may occur between rapidly evolving components of the antiviral RNAi pathway of Drosophila and viral genes that antagonize it. We have recently shown that viral protein 1 (VP1) of Drosophila melanogaster Nora virus (DmelNV) suppresses Argonaute-2 (AGO2)-mediated target RNA cleavage (slicer activity) to antagonize antiviral RNAi. Here we show that viral AGO2 antagonists of divergent Nora-like viruses can have host specific activities. We have identified novel Nora-like viruses in wild-caught populations of D. immigrans (DimmNV) and D. subobscura (DsubNV) that are 36% and 26% divergent from DmelNV at the amino acid level. We show that DimmNV and DsubNV VP1 are unable to suppress RNAi in D. melanogaster S2 cells, whereas DmelNV VP1 potently suppresses RNAi in this host species. Moreover, we show that the RNAi suppressor activity of DimmNV VP1 is restricted to its natural host species, D. immigrans. Specifically, we find that DimmNV VP1 interacts with D. immigrans AGO2, but not with D. melanogaster AGO2, and that it suppresses slicer activity in embryo lysates from D. immigrans, but not in lysates from D. melanogaster. This species-specific interaction is reflected in the ability of DimmNV VP1 to enhance RNA production by a recombinant Sindbis virus in a host-specific manner. Our results emphasize the importance of analyzing viral RNAi suppressor activity in the relevant host species. We suggest that rapid co-evolution between RNA viruses and their hosts may result in host species-specific activities of RNAi suppressor proteins, and therefore that viral RNAi suppressors could be host-specificity factors.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Joël T
authors.initials: JT
authors.lastname: van Mierlo
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Gijs J
authors.initials: GJ
authors.lastname: Overheul
authors.affiliation: Institut Pasteur, Viruses and RNA interference Unit and Centre National de la Recherche Scientifique, UMR 3569, Paris, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Obadia
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Koen W R
authors.initials: KW
authors.lastname: van Cleef
authors.affiliation: Institute of Evolutionary Biology and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Claire L
authors.initials: CL
authors.lastname: Webster
authors.affiliation: Institut Pasteur, Viruses and RNA interference Unit and Centre National de la Recherche Scientifique, UMR 3569, Paris, France.
authors.forename: Maria-Carla
authors.initials: MC
authors.lastname: Saleh
authors.affiliation: Institute of Evolutionary Biology and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Obbard
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: van Rij
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D008969:Molecular Sequence Data; D034622:RNA Interference; D012328:RNA Viruses / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C433807:AGO2 protein, Drosophila; D060565:Argonaute Proteins; D029721:Drosophila Proteins; D014764:Viral Proteins