The Baculovirus Antiapoptotic p35 Protein Functions as an Inhibitor of the Host RNA Interference Antiviral Response

Mehrabadi, Mohammad; Hussain, Mazhar; Matindoost, Leila; Asgari, Sassan

doi:10.1128/jvi.00802-15

Cited by 64 publications

(52 citation statements)

References 53 publications

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“…However, the expression increased gradually until day 7 postinfection. Suppressors of host RNAi have been reported for other large DNA viruses, for example, iridoviruses and baculoviruses (53,54). The evolutionary conservation of an RNAi suppressor in all ascovirus species implies exposure of ascoviruses to the host RNAi machinery, and probably the dsRNA, the pathway inducer signal, originates from the bidirectional transcription, the main source of dsRNA in the case of DNA viruses (55)(56)(57)(58).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of the Spodoptera frugiperda AscovirusIn VivoProvides Insights into How Its Apoptosis Inhibitors and Caspase Promote Increased Synthesis of Viral Vesicles and Virion Progeny

Zaghloul

Hice

Arensburger

et al. 2017

J Virol

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Ascoviruses are ds DNA viruses that attack caterpillars and differ from all other viruses by inducing nuclear lysis followed by cleavage of host cells into numerous anucleate vesicles in which virus replication continues as these grow in the blood. Ascoviruses are also unusual in that most encode apoptosis inhibitors and caspase or caspase-like proteins. A robust cell line to study the novel molecular biology of ascovirus replication is lacking. Therefore, we used strand-specific RNA-Seq to study transcription in third instars of infected with the Spodoptera frugiperda ascovirus, a member of the type species, (SfAV-1a), sampling transcripts at different time points after infection. We targeted transcription of two types of SfAV-1a genes; first, 44 core genes that occur in several ascovirus species, and second, 26 genes predicted to have metabolic functions likely involved in synthesizing viral vesicle membranes. Gene cluster analysis showed differences in temporal expression of SfAV-1a genes, enabling their assignment to three temporal classes; early, late and very late. Inhibitors of apoptosis (IAP-like proteins; ORF016, ORF025 and ORF074) were expressed early, whereas its caspase (ORF073) was expressed very late, which correlated with apoptotic events leading to viral vesicle formation. Expression analysis revealed that a Diedel gene homolog (ORF121), the only known "virokine," was highly expressed, implying this ascovirus protein helps evade innate host immunity. Lastly, single-nucleotide resolution of RNA-Seq data revealed 15 bicistronic and tricistronic messages along the genome, an unusual occurrence for large ds DNA viruses. Unlike all other DNA viruses, ascoviruses code for an executioner caspase, apparently involved in a novel cytopathology in which viral replication induces nuclear lysis followed by cell cleavage yielding numerous large anucleate viral vesicles that continue to produce virions. Our transcriptome analysis of genome expression by the Spodoptera frugiperda ascovirus shows that inhibitors of apoptosis are expressed first enabling viral replication to proceed, after which the SfAV-1a caspase is synthesized, leading to viral vesicle synthesis and subsequent extensive production of progeny virions. Moreover, we detected numerous bicistronic and tricistronic mRNA messages in the ascovirus transcriptome, implying ascoviruses use other non-canonical translational mechanisms such as Internal Ribosome Entry Site (IRES). These results provide the first insights into the molecular biology of a unique coordinated gene expression pattern in which cell architecture is markedly modified, more than in any other known eukaryotic virus, to promote viral reproduction and transmission.

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Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis of the Spodoptera frugiperda AscovirusIn VivoProvides Insights into How Its Apoptosis Inhibitors and Caspase Promote Increased Synthesis of Viral Vesicles and Virion Progeny

Zaghloul

Hice

Arensburger

et al. 2017

J Virol

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“…Jayachandran et al (16) found abundant 20-nt vsRNAs following infection of Helicoverpa armigera (Lepidoptera; Noctuidae) with the H. armigera single nucleopolyhedrovirus (HaSNPV). In the lepidopteran Sf9 cell line, the predominant size class of baculovirus-derived vsRNAs was also 20 nt in length (39).…”

Section: Discussionmentioning

confidence: 99%

Viral Small-RNA Analysis of Bombyx mori Larval Midgut during Persistent and Pathogenic Cytoplasmic Polyhedrosis Virus Infection

Zografidis

Nieuwerburgh

Κολλιοπούλου

et al. 2015

J Virol

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The lepidopteran innate immune response against RNA viruses remains poorly understood, while in other insects several studies have highlighted an essential role for the exo-RNAi pathway in combating viral infection. Here, by using deep-sequencing technology for viral small-RNA (vsRNA) assessment, we provide evidence that exo-RNAi is operative in the silkworm Bombyx mori against both persistent and pathogenic infection of B. mori cytoplasmic polyhedrosis virus (BmCPV) which is characterized by a segmented double-stranded RNA (dsRNA) genome. Further, we show that Dicer-2 predominantly targets viral dsRNA and produces 20-nucleotide (nt) vsRNAs, whereas an additional pathway is responsive to viral mRNA derived from segment 10. Importantly, vsRNA distributions, which define specific hot and cold spot profiles for each viral segment, to a considerable degree overlap between Dicer-2-related (19 to 21 nt) and Dicer-2-unrelated vsRNAs, suggesting a common origin for these profiles. We found a degenerate motif significantly enriched at the cut sites of vsRNAs of various lengths which link an unknown RNase to the origins of vsRNAs biogenesis and distribution. Accordingly, the indicated RNase activity may be an important early factor for the host's antiviral defense in Lepidoptera. Central to the defense of insects against RNA viruses is the triggering of the so-called exogenous RNA interference pathway (exo-RNAi), by which viral double-stranded RNA (dsRNA) is cleaved intracellularly into viral small interfering RNAs (siRNAs) that in turn silence homologous transcripts (1). It is established that Dicer-2, a cytoplasmic RNase III class enzyme, recognizes and cuts successively the dsRNA template to produce small interfering RNA duplexes of ϳ21 nucleotides (nt) characterized by a signature of 2-nt 3=-hydroxyl overhangs (2). These duplexes are subsequently incorporated into the effector complex RISC (RNA-induced silencing complex) via interactions with Argonaute-2, which, upon discarding one of the two strands (passenger strand), is followed by selection and cleavage of viral sequences bearing perfect complementarity to the remaining strand (guide strand) (1, 3). Dicer-2 may act upon the genome of the virus itself-as in the case of dsRNA viruses-and/or on viral replication and transcription intermediates, although structured, single-stranded RNA (ssRNA) may also be utilized (4). Interestingly, several deepsequencing data have revealed that approximately 18-to 30-nt viral small RNAs (vsRNAs) of infected insects are not evenly distributed along the genomes but map preferentially in distinct genomic areas (hot spots) versus genomic stretches with unmapped or less-mapped vsRNAs (cold spots) (4-13). The origin of these profiles, as well as the hypothetical functional distinction between vsRNAs deriving from hot or cold spots, remains substantially elusive, although hot spots near the end of the genome have been attributed to structured regulatory viral regions (14) and an RNAi decoy-like mechanism driven by abundant vsRNAs ...

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“…During infection in vertebrates, the baculovirus P33 (encoded by AcMNPV orf92 ) is involved in processes such as cell-cycle regulation, apoptosis, differentiations and oncogenic transformations [ 124 ]. P35-mediated inhibition of the evolutionary conserved ICE/ICE-like proteases [ 125 ] results in increased AcMNPV titers and allows successful virus infection in the host [ 126 ]. Neither MdSGHV nor GpSGHV encodes P35 or P49 homologs, which probably underscores the functional and evolutionary differences between SGHVs and baculoviruses.…”

Section: Evolution Of Host’s Apoptosis and Sghvs Escape Strategiesmentioning

confidence: 99%

Coevolution of hytrosaviruses and host immune responses

et al. 2018

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BackgroundHytrosaviruses (SGHVs; Hytrosaviridae family) are double-stranded DNA (dsDNA) viruses that cause salivary gland hypertrophy (SGH) syndrome in flies. Two structurally and functionally distinct SGHVs are recognized; Glossina pallidipes SGHV (GpSGHV) and Musca domestica SGHV (MdSGHV), that infect the hematophagous tsetse fly and the filth-feeding housefly, respectively. Genome sizes and gene contents of GpSGHV (~ 190 kb; 160–174 genes) and MdSGHV (~ 124 kb; 108 genes) may reflect an evolution with the SGHV-hosts resulting in differences in pathobiology. Whereas GpSGHV can switch from asymptomatic to symptomatic infections in response to certain unknown cues, MdSGHV solely infects symptomatically. Overt SGH characterizes the symptomatic infections of SGHVs, but whereas MdSGHV induces both nuclear and cellular hypertrophy (enlarged non-replicative cells), GpSGHV induces cellular hyperplasia (enlarged replicative cells). Compared to GpSGHV’s specificity to Glossina species, MdSGHV infects other sympatric muscids. The MdSGHV-induced total shutdown of oogenesis inhibits its vertical transmission, while the GpSGHV’s asymptomatic and symptomatic infections promote vertical and horizontal transmission, respectively. This paper reviews the coevolution of the SGHVs and their hosts (housefly and tsetse fly) based on phylogenetic relatedness of immune gene orthologs/paralogs and compares this with other virus-insect models.ResultsWhereas MdSGHV is not vertically transmitted, GpSGHV is both vertically and horizontally transmitted, and the balance between the two transmission modes may significantly influence the pathogenesis of tsetse virus. The presence and absence of bacterial symbionts (Wigglesworthia and Sodalis) in tsetse and Wolbachia in the housefly, respectively, potentially contributes to the development of SGH symptoms. Unlike MdSGHV, GpSGHV contains not only host-derived proteins, but also appears to have evolutionarily recruited cellular genes from ancestral host(s) into its genome, which, although may be nonessential for viral replication, potentially contribute to the evasion of host’s immune responses. Whereas MdSGHV has evolved strategies to counteract both the housefly’s RNAi and apoptotic responses, the housefly has expanded its repertoire of immune effector, modulator and melanization genes compared to the tsetse fly.ConclusionsThe ecologies and life-histories of the housefly and tsetse fly may significantly influence coevolution of MdSGHV and GpSGHV with their hosts. Although there are still many unanswered questions regarding the pathogenesis of SGHVs, and the extent to which microbiota influence expression of overt SGH symptoms, SGHVs are attractive ‘explorers’ to elucidate the immune responses of their hosts, and the transmission modes of other large DNA viruses.

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The Baculovirus Antiapoptotic p35 Protein Functions as an Inhibitor of the Host RNA Interference Antiviral Response

Cited by 64 publications

References 53 publications

Transcriptome Analysis of the Spodoptera frugiperda AscovirusIn VivoProvides Insights into How Its Apoptosis Inhibitors and Caspase Promote Increased Synthesis of Viral Vesicles and Virion Progeny

Transcriptome Analysis of the Spodoptera frugiperda AscovirusIn VivoProvides Insights into How Its Apoptosis Inhibitors and Caspase Promote Increased Synthesis of Viral Vesicles and Virion Progeny

Viral Small-RNA Analysis of Bombyx mori Larval Midgut during Persistent and Pathogenic Cytoplasmic Polyhedrosis Virus Infection

Coevolution of hytrosaviruses and host immune responses

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