Induction and Suppression of NF-kappa B Signalling by a DNA Virus of Drosophila

Interactions between the insect immune system and RNA viruses have been extensively studied in Drosophila, where RNA interference, NF-κB and JAK-STAT pathways underlie antiviral immunity. In response to RNA interference, insect viruses have convergently evolved suppressors of this pathway that act by diverse mechanisms to permit viral replication. However, interactions between the insect immune system and DNA viruses have received less attention, primarily because few Drosophila-infecting DNA virus isolates are available. Here, we use a recently-isolated DNA virus of Drosophila melanogaster, Kallithea virus (family Nudiviridae), to probe known antiviral immune responses and virus evasion tactics in the context of DNA virus infection. We find that fly mutants for RNA interference and Immune deficiency (Imd), but not Toll, pathways are more susceptible to Kallithea virus infection. We identify the Kallithea virus-encoded protein gp83 as a potent inhibitor of Toll signalling, suggesting that Toll mediates antiviral defense against Kallithea virus infection, but that it is suppressed by the virus. We find that Kallithea virus gp83 inhibits Toll signalling through the regulation of NF-κB transcription factors. Furthermore, we find that gp83 of the closely related Drosophila innubila nudivirus (DiNV) suppresses D. melanogaster Toll signalling, suggesting an evolutionary conserved function of Toll in defense against DNA viruses. Together, these results provide a broad description of known antiviral pathways in the context of DNA virus infection and identify the first Toll pathway inhibitor in a Drosophila virus, extending the known diversity of insect virus-encoded immune inhibitors.Importance Co-evolution of multicellular organisms and their natural viruses may lead to an intricate relationship in which host survival requires effective immunity, and virus survival depends on evasion of such responses. Insect antiviral immunity, and reciprocal virus immune suppression tactics, have been well-studied in Drosophila melanogaster, primarily during RNA, but not DNA, virus infection. Therefore, we describe interactions between a recently-isolated Drosophila DNA virus (Kallithea virus - KV) and immune processes known to control RNA viruses, such as RNAi and Imd pathways. We find that KV suppresses the Toll pathway, and identify gp83 as a KV-encoded protein that underlies this suppression. This immunosuppressive ability is conserved in another nudivirus, suggesting the Toll pathway has conserved antiviral activity against DNA nudiviruses, which have evolved suppressors in response. Together, these results indicate that DNA viruses induce and suppress NF-κB responses, and advance the application of KV as a model to study insect immunity.