Intriguingly, the closest insect ortholog of the intracellular sensors RIG-I and MDA5 is Dicer-2 and virus infection in Drosophila initiates a specific transcriptional response, including the induction of the antiviral effector Vago, whose expression is dependent MK-2206 supplier upon Dicer-2 [32]. This suggests that Dicer-2-driven signaling contributes to the induction of a specific set of antiviral effectors during infection. The spectrum of Dicer-2-dependent downstream signaling events, and whether this function of Dicer-2 is conserved in shrimp and

other invertebrates, has yet to be elucidated. One potential mechanism to explain the nonspecific immunity triggered by dsRNA in shrimp is that the detection

of dsRNA, either by Dicer-2 or an additional sensor (Fig. 1B), triggers a feed-forward loop, whereby the RNAi machinery itself is transcriptionally upregulated, thus setting up a cellular environment that is poised to attack and degrade additional foreign nucleic acids. A recent study found that injection of dsRNA leads to the specific upregulation of Ago2 and Sid-1 mRNA in the shrimp Litopenaeus vannamei [28]. Moreover, WSSV infection induced Dicer-2 mRNA in Litopenaeus vannamei [33]. Recent work in our laboratory has shown that virus infection of Drosophila induces the upregulation of the RNAi pathway components Dicer-2 and Ars2 [34]. However, the viral PAMPs involved in inducing this response are not likely dsRNA, since the transcriptional upregulation Daporinad order Bumetanide of antiviral effectors occurs prior to viral replication. The shrimp Ars2 ortholog was recently identified and cloned [35]; it will therefore be important to investigate whether Ars2 and additional members of the RNA-silencing pathways in shrimp are regulated by infection. Although vsiRNAs are produced in an infected cell, whether these small RNAs or other viral RNA species, such as dsRNA, are released from infected cells

remains unknown. It is possible that the release of nucleic acids from infected cells alerts neighboring cells or even distant cells to the presence of infection. Accordingly, a local infection could lead to systemic antiviral defenses. This would also present opportunities for synergies between sequence-specific responses, which act cell-autonomously, and sequence-independent responses, which generate a nonautonomous anti-viral state. Studies in Drosophila have demonstrated that systemic RNAi can suppress viral replication [36]. Further exploration of these possibilities will likely reveal additional aspects of immunity to viral pathogens, but altogether will reinforce the fact that the initiation of antiviral immunity in response to the detection of viral PAMPs, including dsRNA, is a defense strategy conserved through evolution.