Antiviral immunity in drosophila

Kemp, Cordula; Imler, Jean‐Luc

doi:10.1016/j.coi.2009.01.007

Cited by 130 publications

(135 citation statements)

References 53 publications

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“…2003). The antiviral immune response of insects is poorly understood compared to antibacterial and antifungal immunity (Kemp & Imler 2009); therefore, this can lead to new insights into the evolution of resistance to infection, as well as the mechanisms of virus interaction with hosts.…”

Section: Discussionmentioning

confidence: 99%

The genetic architecture of resistance to virus infection in Drosophila

et al. 2016

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Variation in susceptibility to infection has a substantial genetic component in natural populations, and it has been argued that selection by pathogens may result in it having a simpler genetic architecture than many other quantitative traits. This is important as models of host–pathogen co‐evolution typically assume resistance is controlled by a small number of genes. Using the Drosophila melanogaster multiparent advanced intercross, we investigated the genetic architecture of resistance to two naturally occurring viruses, the sigma virus and DCV (Drosophila C virus). We found extensive genetic variation in resistance to both viruses. For DCV resistance, this variation is largely caused by two major‐effect loci. Sigma virus resistance involves more genes – we mapped five loci, and together these explained less than half the genetic variance. Nonetheless, several of these had a large effect on resistance. Models of co‐evolution typically assume strong epistatic interactions between polymorphisms controlling resistance, but we were only able to detect one locus that altered the effect of the main effect loci we had mapped. Most of the loci we mapped were probably at an intermediate frequency in natural populations. Overall, our results are consistent with major‐effect genes commonly affecting susceptibility to infectious diseases, with DCV resistance being a near‐Mendelian trait.

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Section: Discussionmentioning

confidence: 99%

The genetic architecture of resistance to virus infection in Drosophila

et al. 2016

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“…In contrast to the protein‐based type I IFN system found in vertebrates, antiviral immunity in plants and invertebrates relies on an RNA‐based, sequence‐specific defence pathway known as RNA interference (RNAi; Ding & Voinnet, 2007; Kemp & Imler, 2009; Wilson & Doudna, 2013; tenOever, 2016). The importance of RNAi in antiviral defence in these organisms is underscored by the evolution in most plant and insect viruses of viral‐encoded RNAi antagonists, known as viral suppressors of RNA silencing (VSRs) that block various steps in the RNAi pathway (Ding & Voinnet, 2007; Wu et al , 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The importance of RNAi in antiviral defence in these organisms is underscored by the evolution in most plant and insect viruses of viral‐encoded RNAi antagonists, known as viral suppressors of RNA silencing (VSRs) that block various steps in the RNAi pathway (Ding & Voinnet, 2007; Wu et al , 2010). In the absence of VSRs, viral dsRNA generated during viral infection and replication is rapidly cleaved by the type III ribonuclease Dicer into virus‐derived small interfering RNAs (viRNAs), which are loaded onto an Argonaute (Ago) family protein to form the RNA‐induced silencing complex (RISC) that targets complementary viral RNA for cleavage (Ding & Voinnet, 2007; Kemp & Imler, 2009; Wilson & Doudna, 2013; tenOever, 2016). Interestingly, the RLR family and Dicer share the conserved DExD/H helicase domain and have comparable substrate specificity (dsRNA) although their respective functions (signalling versus catalytic processing) are distinct (MacKay et al , 2014; Paro et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

et al. 2018

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In vertebrates, the presence of viral RNA in the cytosol is sensed by members of the RIG‐I‐like receptor (RLR) family, which signal to induce production of type I interferons (IFN). These key antiviral cytokines act in a paracrine and autocrine manner to induce hundreds of interferon‐stimulated genes (ISGs), whose protein products restrict viral entry, replication and budding. ISGs include the RLRs themselves: RIG‐I, MDA5 and, the least‐studied family member, LGP2. In contrast, the IFN system is absent in plants and invertebrates, which defend themselves from viral intruders using RNA interference (RNAi). In RNAi, the endoribonuclease Dicer cleaves virus‐derived double‐stranded RNA (dsRNA) into small interfering RNAs (siRNAs) that target complementary viral RNA for cleavage. Interestingly, the RNAi machinery is conserved in mammals, and we have recently demonstrated that it is able to participate in mammalian antiviral defence in conditions in which the IFN system is suppressed. In contrast, when the IFN system is active, one or more ISGs act to mask or suppress antiviral RNAi. Here, we demonstrate that LGP2 constitutes one of the ISGs that can inhibit antiviral RNAi in mammals. We show that LGP2 associates with Dicer and inhibits cleavage of dsRNA into siRNAs both in vitro and in cells. Further, we show that in differentiated cells lacking components of the IFN response, ectopic expression of LGP2 interferes with RNAi‐dependent suppression of gene expression. Conversely, genetic loss of LGP2 uncovers dsRNA‐mediated RNAi albeit less strongly than complete loss of the IFN system. Thus, the inefficiency of RNAi as a mechanism of antiviral defence in mammalian somatic cells can be in part attributed to Dicer inhibition by LGP2 induced by type I IFNs. LGP2‐mediated antagonism of dsRNA‐mediated RNAi may help ensure that viral dsRNA substrates are preserved in order to serve as targets of antiviral ISG proteins.

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“…These can serve as substrates for Dicer to generate virus‐derived siRNAs (viRNAs) (Ding & Voinnet, 2007; Kemp & Imler, 2009; Swarts et al , 2014; tenOever, 2016) that are loaded onto RISC and target complementary viral RNA to block virus replication. Indeed, viRNA‐mediated RNAi constitutes the primary antiviral defence strategy of plants and invertebrates (Ding & Voinnet, 2007; Kemp & Imler, 2009; Swarts et al , 2014; tenOever, 2016). Consequently, plant and insect viruses have evolved virulence factors called viral suppressors of RNA silencing (VSRs) that block various steps of the antiviral RNAi mechanism (Haasnoot et al , 2007; Wu et al , 2010).…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the type I interferon pathway reveals long double‐stranded RNA‐mediated RNA interference in mammalian cells

et al. 2016

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RNA interference (RNAi) elicited by long double‐stranded (ds) or base‐paired viral RNA constitutes the major mechanism of antiviral defence in plants and invertebrates. In contrast, it is controversial whether it acts in chordates. Rather, in vertebrates, viral RNAs induce a distinct defence system known as the interferon (IFN) response. Here, we tested the possibility that the IFN response masks or inhibits antiviral RNAi in mammalian cells. Consistent with that notion, we find that sequence‐specific gene silencing can be triggered by long dsRNAs in differentiated mouse cells rendered deficient in components of the IFN pathway. This unveiled response is dependent on the canonical RNAi machinery and is lost upon treatment of IFN‐responsive cells with type I IFN. Notably, transfection with long dsRNA specifically vaccinates IFN‐deficient cells against infection with viruses bearing a homologous sequence. Thus, our data reveal that RNAi constitutes an ancient antiviral strategy conserved from plants to mammals that precedes but has not been superseded by vertebrate evolution of the IFN system.

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Antiviral immunity in drosophila

Cited by 130 publications

References 53 publications

The genetic architecture of resistance to virus infection in Drosophila

The genetic architecture of resistance to virus infection in Drosophila

The RIG‐I‐like receptor LGP2 inhibits Dicer‐dependent processing of long double‐stranded RNA and blocks RNA interference in mammalian cells

Inactivation of the type I interferon pathway reveals long double‐stranded RNA‐mediated RNA interference in mammalian cells

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