The RSAR of invertebrates is rapid, effective and adaptive. In contrast to the broad-spectrum innate immunity in Drosophila and mosquitoes (Christophides et al., 2002; Hoffmann, 2003), RSAR has features similar to the peptide-based adaptive immunity in vertebrates (Whitton & Oldstone, 2001). The specificity determinants of RSAR are siRNAs, which are derived and processed from the invading virus. After being uploaded into RISC, these virus-specific siRNAs selectively recruit target viral genomic and/or messenger RNAs by base-pairing for RISC-mediated destruction. At the whole-organism level, RNA silencing may also provide a long-term memory, analogous to the lifetime maintenance of specific virus resistance in plants recovered from a virulent primary infection (Covey et al., 1997; Ratcliff et al., 1997, 1999; Xin & Ding, 2003). However, while the peptide-based immunity in vertebrates usually takes more than a week to respond (Whitton & Oldstone, 2001), the RNA-silencing response in fruit flies and mosquitoes is capable of a rapid and complete virus clearance in single cells (Li et al., 2002, 2004), which is similar to the innate immunity. In this regard, it is possible that RNA silencing may contribute to, or be part of, the robust innate immunity occurring at early stages of viral infection in vertebrates (Parham, 2003). This is supported in part by the recent demonstration that a number of mammalian viruses encode suppressors of RNA silencing that were previously shown to inhibit the interferon-regulated innate immunity in vertebrates (Li et al., 2004).
It is known that common components, such as siRNA, Dicer and Argonaute proteins, are involved in PTGS in plants and RNAi in animals (Denli & Hannon, 2003; Tang et al., 2003; Vance & Vaucheret, 2001). Suppression of RSAR in both plants and invertebrates by the same B2 protein provides direct experimental evidence that at least some aspects are conserved in the RNA-silencing pathway between the plant and animal kingdoms (Li et al., 2002; Lindenbach & Rice, 2002). However, it appears that at the single-cell level, RSAR targeting of infecting viruses is not as potent in plants as in insects. For example, most of the plant viral suppressors characterized to date interfere with the cell-to-cell and long-distance spread of RNA silencing, which may explain why plant virus mutants that lack a functional suppressor do not exhibit obvious defect in single cells (Li & Ding, 2001; Silhavy et al., 2002). This is in contrast to an essential role for B2 suppression in nodaviral infection of insect cells (Li et al., 2002, 2004). It is possible that organisms that do not carry a cellular RdRP, such as fruit flies and mosquitoes, have evolved a more efficient multiple-turnover RISC capable of a potent intracellular silencing, which becomes the target of animal viral suppressors.
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