Antiviral immunity in drosophila

Abstract

Genetic analysis of the drosophila antiviral response indicates that RNA interference plays a major role. This contrasts with the situation in mammals, where interferon-induced responses mediate innate antiviral host-defense. An inducible response also contributes to antiviral immunity in drosophila, and similarities in the sensing and signaling of viral infection are becoming apparent between drosophila and mammals. In particular, DExD/H box helicases appear to play a crucial role in the cytosolic detection of viral RNAs in flies and mammals.

Figure 1

Degradation of viral nucleic acids by RNA interference. Dicer-2 senses double stranded (ds)RNA produced by the viral RNA-dependent RNA-polymerase (vRDRP) during replication of the virus. Following recognition, the RNaseIII enzyme Dicer-2, which is found in a complex with the dsRNA binding protein R2D2, processes dsRNA into duplex siRNAs (left panel). The guide strand of these siRNAs is then incorporated in the RNA induced silencing complex (RISC), while the passenger strand is degraded (not shown on the figure). The loaded RISC complex mediates sequence specific slicing of viral ssRNA by its core component AGO2 (right panel).

Figure 2

A model for the Dicer-2 mediated control of FHV infection. The viral suppressor of RNAi B2 is associated with the viral RDRP, which is anchored in the outer mitochondrial membrane. B2 binds to dsRNA replicative intermediates as they are synthesized, thus protecting them from the action of Dicer-2 (left panel). When B2 is mutated, Dicer-2 binds the nascent dsRNA replication intermediates and generates massive amounts of siRNAs corresponding to the 5′ end of the genome, leading to abortive replication and protection of the infected cells (right panel).

Figure 3

Sensing of viral nucleic acids by DExD/H box helicases in drosophila and mammals. dsRNA is detected by Dicer-2 and RLRs (RIG-I and MDA5) in flies and mammals, respectively. These molecules contain phylogenetically related DExD/H box helicase domains, which mediate a conformational change in response to interaction with viral RNAs (dsRNA or single stranded RNA with a 5′ triphosphate extremity in the case of RIG-I). In drosophila (left panel), Dicer-2 processes dsRNA into siRNAs, and triggers an unidentified signal that leads to the inducible expression of the gene Vago, which controls the viral load in the fat body of infected flies. In mammals (right panel), RLRs activate the signal transducer IPS-1 and transcription factors of the IRF family, leading to production of interferons.