Dicer-2-Dependent Generation of Viral DNA from Defective Genomes of RNA Viruses Modulates Antiviral Immunity in Insects

Poirier, Enzo Z.; Goic, Bertsy; Tomé-Poderti, Lorena; Frangeul, Lionel; Boussier, Jérémy; Gausson, Valérie; Blanc, Hervé; Vallet, Thomas; Loyd, Hyelee; Levi, Laura; Lanciano, Sophie; Baron, Chloé S.; Merkling, Sarah H.; Lambrechts, Louis; Mirouze, Marie; Carpenter, Susan; Vignuzzi, Marco; Saleh, María-Carla

doi:10.1016/j.chom.2018.02.001

Cited by 132 publications

(187 citation statements)

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“…Similar to the RIG-I and MDA5 PRRs in mammals, insects sense viral RNA through the protein Dicer-2. This protein processes the viral RNA into small interfering RNAs that protect insects from re-infection with the same virus 103 . DVGs are the primary targets for Dicer-2 (ref.…”

Section: Moi Multiplicity Of Infection Ratio Of Infectious Virus Tomentioning

confidence: 99%

“…DVGs are the primary targets for Dicer-2 (ref. 103 ). These observations indicate that the immunostimulatory activity of DVGs is widespread and may have a significant impact on the spread of pathogens within and across species.…”

Section: Moi Multiplicity Of Infection Ratio Of Infectious Virus Tomentioning

confidence: 99%

“…Recent work in insects suggests that DVGs, which are a preferred template for the generation of the viral DNA form of RNA viruses, provide additional substrate to help boost the RNA interference response that is responsible for viral persistence in insects 103 . Indeed, it was shown that a change in the amount of viral DNA generated during RNA virus infection in Drosophila, altered the persistence and kinetics of a wild-type RNA virus infection.…”

Section: Impact On Viral Evolution and Dynamicsmentioning

confidence: 99%

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Defective viral genomes are key drivers of the virus–host interaction

2019

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Viruses survive often harsh host environments, yet we know little about the strategies they utilize to adapt and subsist given their limited genomic resources. We are beginning to appreciate the surprising versatility of viral genomes and how replicationcompetent and -defective virus variants can provide means for adaptation, immune escape and virus perpetuation. This Review summarizes current knowledge of the types of defective viral genomes generated during the replication of RNA viruses and the functions that they carry out. We highlight the universality and diversity of defective viral genomes during infections and discuss their predicted role in maintaining a fit virus population, their impact on human and animal health, and their potential to be harnessed as antiviral tools. Review ARticleNATuRe MicRoBiology extinction interfere with replication of a wild-type viral genome 29,30 . Hypermutations and mutations leading to frame shifts also result in defective viruses 31 (Fig. 1a). One example is mutations introduced by the cellular protein APOBEC3G into pro-retroviruses 32 . APOBEC3G deaminates deoxycytidine nucleotides in the viral DNA, leading to hypermutations that interfere with the ability of the viral genome to integrate into the host genome and replicate. Interestingly, in opposition to an interfering activity for these mutated pro-viruses, it has been proposed that defective proviruses enhance fitness and that complementation among them drives viral persistence and pathogenesis 33,34 .Deletions. The genomic viral species most commonly referred to as DVGs are truncated viral genomes resulting from large internal deletions occurring during viral replication. Deletion DVGs tend to bear single large truncations that remove several or all essential genes required for self-propagation while retaining 5′ and 3′ ends as well as other RNA structural elements required for polymerase binding, replication and/or packaging [35][36][37] . Multiple variants also exist, including DVGs that can be described as 'mosaic' in that they appear to be the result of multiple recombination and rearrangement events, including deletions, insertions, duplications and even inversions of parts of the genome [38][39][40] (Fig. 1b). Copy-backs.Copy-back and snap-back DVGs are rearranged genomes in which a sequence is duplicated in reverse complement to create theoretical stem-like structures (panhandle structures for copy-back DVGs or hairpin structures for snap-back DVGs) 41-43 . Copy-back DVGs have been reported in many negative-sense (ns) RNA viruses and are generated from the 5′ end of the genome in a process that produces DVGs with complementary 3′ and 5′ termini 44,45 . If the complementary region of the DVG comprises almost the entire sequence, the DVG can be further characterized as a snap-back DVG 43 (Fig. 1c). Copy-back DVGs are predicted to be generated when the viral RNA-dependent RNA polymerase (RdRP) detaches from the template and reattaches to the nascent strand, copying back the end of the genome 42,46 .

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Section: Moi Multiplicity Of Infection Ratio Of Infectious Virus Tomentioning

confidence: 99%

Section: Moi Multiplicity Of Infection Ratio Of Infectious Virus Tomentioning

confidence: 99%

Section: Impact On Viral Evolution and Dynamicsmentioning

confidence: 99%

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Defective viral genomes are key drivers of the virus–host interaction

2019

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“…This dynamic is likely also true in the context of negativesense RNA virus infection in arthropods and/or plants were RNAi is the dominant antiviral defense system (tenOever, 2016). In this arena, DVG production has been shown to serve as a substrate for the generation of siRNAs (Poirier et al, 2018). For this reason, many antagonists such as NS1 have been found to interfere with both RNAi and interferon as these two systems are dependent on the availability of viral RNA substrates (Li et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

An inability to maintain the ribonucleoprotein genomic structure is responsible for host detection of negative-sense RNA viruses

Blanco-Melo

Nilsson-Payant

Uhl

et al. 2020

Preprint

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Defective viral genomes and viral antagonists are key determinants of the host antiviral responseThe host response and defective viral genome generation further exasperate NP availability NP is an optimal drug target for the whole phylum of negative-sense RNA viruses SUMMARY Cellular biology has a uniformity not shared amongst viruses. This is perhaps best exemplified by negative-sense RNA viruses that encode their genetic material as a ribonucleoprotein complex composed of genome, RNA-dependent RNA polymerase, and the nucleoprotein. Here we demonstrate that limiting nucleoprotein availability not only universally culminates in a replicative catastrophe for negative-sense RNA viruses, but it results in the production of aberrant genomic material and induction of the interferonbased host defenses. This dynamic illustrates the tremendous stress imposed on negative-sense RNA viruses during replication as genomic products accumulate in an environment that requires an increasing demand on nucleoprotein availability. We show that limiting NP by RNA interference or drug targeting blocks replication and primes neighboring cells through the production of interferon. Together, these results demonstrate that the nucleoprotein represents the Achilles heel of the entire phylum of negative-sense RNA viruses. Here we establish this principle for a diverse collection of human pathogens and propose that the nucleoprotein should be a primary target for the development of future antiviral drugs. Manuscript

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“…Later, a particularly common deletion spanning from the nsP1-E1 genes of the SINV genome was described in the context of a low-fidelity SINV polymerase mutant (35). More recently, CHIKV has been shown to generate recombinant RNAs in tissue culture, especially RNAs featuring complex duplication/deletion events in the 3’UTR (35–40). While D-RNAs have yet been described for CHIKV in either natural or laboratory animal infections, D-RNAs generated in vivo have been identified for other alphaviruses.…”

Section: Introductionmentioning

confidence: 99%

Differential alphavirus defective RNA diversity between intracellular and encapsidated compartments is driven by subgenomic recombination events

Langsjoen

Muruato

Kunkel

et al. 2020

Preprint

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Alphaviruses are positive-sense RNA arboviruses that can cause either a chronic arthritis or a 24 potentially lethal encephalitis. Like other RNA viruses, alphaviruses produce truncated, defective 25 genomes featuring large deletions during replication. Defective RNAs (D-RNAs) have primarily been 26 isolated from virions after high-multiplicity of infection passaging. Here, we aimed to characterize both 27 intracellular and packaged viral D-RNA populations during early passage infections under the 28 hypothesis that D-RNAs arise de novo intracellularly that may not be packaged and thus have remained 29 undetected. To this end, we generated NGS libraries using RNA derived from passage 1 (P1) stock 30 chikungunya virus (CHIKV) 181/clone 25, intracellular virus, and encapsidated P2 virus and analyzed 31 samples for D-RNA expression, followed by diversity and differential expression analyses. We found 32 that the diversity of D-RNA species is significantly higher for intracellular D-RNA populations than 33 encapsidated and specific populations of D-RNAs are differentially expressed between intracellular and 34 encapsidated compartments. Importantly, these trends were likewise observed in a murine model of 35 CHIKV 15561 infection, as well as in vitro studies using related Mayaro, Sindbis, and Aura viruses. 36Additionally, we identified a novel subtype of subgenomic D-RNA that are conserved across 37 arthritogenic alphaviruses. D-RNAs specific to intracellular populations were defined by recombination 38 events specifically in the subgenomic region, which was confirmed by direct RNA nanopore sequencing 39 of intracellular CHIKV RNAs. Together, these studies show that only a portion of D-RNAs generated 40 intracellularly are packaged and D-RNAs readily arise de novo in the absence of transmitted template. 41 3 IMPORTANCE 42 Our understanding of viral defective RNAs (D-RNAs), or truncated viral genomes, comes largely from 43 passaging studies in tissue culture under artificial conditions and/or packaged viral RNAs. Here, we 44 show that specific populations of alphavirus D-RNAs arise de novo and that they are not packaged into 45 virions, thus imposing a transmission bottleneck and impeding their prior detection. This raises 46 important questions about the roles of D-RNAs, both in nature and in tissue culture, during viral infection 47 and whether their influence is constrained by packaging requirements. Further, during the course of 48 these studies, we found a novel type of alphavirus D-RNA that is enriched intracellularly; dubbed 49 subgenomic D-RNAs (sgD-RNAs), they are defined by deletion boundaries between capsid/E3 and 50 E1/3'UTR regions and are common to chikungunya, Mayaro, Sindbis, and Aura viruses. These sgD-51 RNAs are enriched intracellularly and do not appear to be selectively packaged, and additionally may 52 exist as subgenome-derived transcripts. 53 Although D-RNAs have been considered an epi-phenomenon of cell-culturing practices, emerging deep 79 sequencing technologies have enabled researchers t...

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Dicer-2-Dependent Generation of Viral DNA from Defective Genomes of RNA Viruses Modulates Antiviral Immunity in Insects

Cited by 132 publications

References 68 publications

Defective viral genomes are key drivers of the virus–host interaction

Defective viral genomes are key drivers of the virus–host interaction

An inability to maintain the ribonucleoprotein genomic structure is responsible for host detection of negative-sense RNA viruses

Differential alphavirus defective RNA diversity between intracellular and encapsidated compartments is driven by subgenomic recombination events

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