Comparison with mammalian antiviral defences

Based on its critical role in the control of viral infection in plants and invertebrates, RNAi is often presented as an evolutionarily conserved antiviral defence. But is RNAi involved in the control of viral infections in mammals? While there is no doubt that RNAi can be used to fight viral infection, when cells are supplied with exogenous siRNAs or small hairpin (sh) RNAs, vertebrate cells apparently cannot process viral RNAs into siRNAs. This probably reflects the fact that vertebrates only have a single Dicer gene, mediating the production of miRNAs, whereas insects and plants have respectively one or three additional Dicer enzymes producing siRNAs. There are several examples in the literature demonstrating that miRNAs can modulate the replication cycle of viruses in mammalian cells (reviewed in Müller and Imler, 2007). The situation closest to that found in insects and plants is that of cellular miR-NAs targeting viral sequences. The role of these miRNAs has been best described in the case of the Indiana strain of VSV, where two miRs, miR24 and miR93, target the L and P genes from the virus. The relevance of this control has been attested by studies using mice containing a hypomorphic mutation of Dicer, which exhibit a higher sensitivity to VSV infection. Importantly, while Dicer mutant macrophages produce five- to 10-fold more VSV than wild-type macrophages, they do not have a general antiviral defect, and produce viral titres similar to the wild-type when challenged with several other viruses (Otsuka et al, 2007). One key question—if cells can use miRNAs to target viral genomes—is why the viruses do not change the target sequence to escape recognition. Viruses are indeed known to rapidly mutate and evolve to adapt to their host. One possible answer is that it is not the miRNA that targets the viral genome, but rather the virus that targets the miRNA, and uses it to modulate its replication, to avoid causing too much damage to its host. In support of this explanation, the New Jersey strain of VSV, which is known to induce a stronger interferon response in cattle than the Indiana strain, cannot be recognized by miR24 and miR93 (Müller and Imler, 2007). A similar situation may occur for hepatitis C virus, where viral genomic RNA is recognized by several cellular miRNAs that have antiviral effects. Interestingly, expression of these miRNAs appears to be regulated by interferons, providing a way for the virus to modulate its effects on the host (Pedersen et al., 2007). In summary, even though there is no question that viruses can be targeted by miRNA in mammalian cells, and even in extreme cases use the immune system to upregu-late some miRNAs, this probably reflects more an adaptation of viruses to their hosts than a bona fide immune response, associated with protection of the host against infections. In this respect, the situation in mammals is different from that in insects and plants.

More similarities between insects and mammals are apparent for the inducible response to viral infection, since the JAK/STAT pathway mediates signalling downstream of many cytokine receptors, including the interferons. In mammals, expression of interferons is mediated by the transcription factors IRF3 and IRF7, which are activated upon sensing viral RNAs in infected cells by the cytosolic DExD/H-box helicases RIG-I or MDA5 (reviewed in Beutler et al, 2007). The fly genome does not encode orthologues of these receptors, nor of IRF transcription factors, suggesting that other mechanisms are involved in the sensing of viruses. Viral nucleic acids are also detected in mammalian cells by the Toll-like receptors TLR3, TLR7, and TLR9. As we have seen above, there is some evidence that the Toll pathway participates in the resistance to DXV infection in flies, suggesting that Toll may detect viral components and regulate expression of cytokines activating the JAK/STAT pathway. However, one must keep in mind that, up to now, Toll in flies has been shown to function like a receptor for the cytokine Spätzle (Weber et al, 2003), rather than like a pattern-recognition receptor.

Another interesting point of comparison between mammals and insects is the function of the induced genes. In mammals, interferon regulates the expression of more than 300 interferon-stimulated genes (ISGs), but most of them remain poorly characterized. In fact, most attention has focused on four major effector molecules that help to contain the viral infection (reviewed in Sadler and Williams, 2008): (1) protein kinase R, which phosphorylates the translation factor eIF2a, and inhibits translation, thus blocking the synthesis of viral proteins; (2) 2'-5' oligoadenylate synthase (OAS), which regulates the activity of RNaseL; (3) the Mx GTPases, which regulate membrane trafficking and can trap essential viral components; and (4) the 15 kDa ubiquitin-like molecule ISG15, which can be conjugated to protein substrates (for example IRF3), resulting in their activation. Importantly, none of these effector molecules are present in Drosophila. Thus, flies appear to rely on specific antiviral mechanisms. The identification of these mechanisms may therefore reveal novel ways to interfere with the viral cycles that could lead to novel ideas for therapeutic intervention.

In summary, even though there appears to be striking conservation of the mechanisms operating during the inducible antiviral response in flies and mammals at the conceptual level (induction of several hundred genes; involvement of a cyto-kine activating the JAK/STAT pathway), important differences are apparent in the sensing of viral infection, and the effector molecules induced by infection. Whether the similarities reflect a common ancestry, or convergent evolution, will become apparent when the mechanisms of the inducible antiviral immunity in flies have been better characterized, and the extent of the similarities/ differences is more apparent.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment