Morphogenesis of the Nodamura virus in the larvae of the lepidopteranGalleria mellonella (L.)

Garzón, S.; Charpentier, G.; Kurstak, Edouard

doi:10.1007/bf01317283

Cited by 23 publications

(27 citation statements)

References 26 publications

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“…While not yet visualized at the ultrastructural level, we hypothesize that the clustered phenotype seen in cultured cells represents the same altered mitochondrial morphology and mitochondrial aggregation previously described for NoV-infected muscle tissue (1,43,44). We further showed that NoV RNA synthesis also localizes to these RdRpinduced mitochondrial networks, further establishing mitochondria as the site of viral RC formation.…”

Section: Discussionmentioning

confidence: 65%

“…Transmission electron micrographs of muscle tissue from NoV-infected mice show localized increases in the number of mitochondria, rearrangement of mitochondrial membranes, and aggregation of mitochondria. Similar rearrangements in muscle tissue are also visible in NoV-infected larvae of the greater wax moth, Galleria mellonella, which exhibit hind segment paralysis upon infection with NoV (1,43,44). However, the role of mitochondria in NoV infection has not been addressed previously.…”

mentioning

confidence: 78%

“…Strikingly, the tissues exhibited progressive disorganization of the muscle fibers and fibrils, as the mitochondria became altered and the cells filled with paracrystalline arrays of progeny viral particles (44). It has been hypothesized that the paralysis seen in these animals is a result of this disruption of the muscle fibrils by altered mitochondria (1,43,44).…”

Section: Discussionmentioning

confidence: 99%

“…NoV replicates in the musculature of the lower back and hind limbs of suckling mice and suckling hamsters, leading to flaccid paralysis of the hind limbs and death (44,85,86). Similarly, viral replication in the muscle tissues of greater wax moth (Galleria mellonella) larvae results in fatal paralysis of the hind segments (1,43,44). In infected muscle cells from mice and G. mellonella larvae, the mitochondria clustered around the nucleus and, late in infection, exhibited altered architecture.…”

Section: Discussionmentioning

confidence: 99%

“…showed close association of NoV particles with ultrastructurally malformed mitochondria, implicating this organelle in the NoV infectious cycle (1,43,44). Additionally, the FHV RdRp associates with mitochondrial membranes in infected Drosophila and yeast cells (32,36).…”

Section: Expression and Localization Kinetics Of The Nov Rdrp In Tranmentioning

confidence: 99%

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Two Membrane-Associated Regions within the Nodamura Virus RNA-Dependent RNA Polymerase Are Critical for both Mitochondrial Localization and RNA Replication

Gant

Moreno

Varela-Ramı́rez

et al. 2014

J Virol

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Viruses with positive-strand RNA genomes amplify their genomes in replication complexes associated with cellular membranes. Little is known about the mechanism of replication complex formation in cells infected with Nodamura virus. This virus is unique in its ability to lethally infect both mammals and insects. In mice and in larvae of the greater wax moth (Galleria mellonella), Nodamura virus-infected muscle cells exhibit mitochondrial aggregation and membrane rearrangement, leading to disorganization of the muscle fibrils on the tissue level and ultimately in hind limb/segment paralysis. However, the molecular basis for this pathogenesis and the role of mitochondria in Nodamura virus infection remains unclear. Here, we tested the hypothesis that Nodamura virus establishes RNA replication complexes that associate with mitochondria in mammalian cells. Our results showed that Nodamura virus replication complexes are targeted to mitochondria, as evidenced in biochemical, molecular, and confocal microscopy studies. More specifically, we show that the Nodamura virus RNA-dependent RNA polymerase interacts with the outer mitochondrial membranes as an integral membrane protein and ultimately becomes associated with functional replication complexes. These studies will help us to understand the mechanism of replication complex formation and the pathogenesis of Nodamura virus for mammals. IMPORTANCEThis study will further our understanding of Nodamura virus (NoV) genome replication and its pathogenesis for mice. NoV is unique among the Nodaviridae in its ability to infect mammals. Here we show that NoV establishes RNA replication complexes (RCs) in association with mitochondria in mammalian cells. These RCs contain newly synthesized viral RNA and feature a physical interaction between mitochondrial membranes and the viral RNA-dependent RNA polymerase (RdRp), which is mediated by two membrane-associated regions. While the nature of the interaction needs to be explored further, it appears to occur by a mode distinct from that described for the insect nodavirus Flock House virus (FHV). The interaction of the NoV RdRp with mitochondrial membranes is essential for clustering of mitochondria into networks that resemble those described for infected mouse muscle and that are associated with fatal hind limb paralysis. This work therefore provides the first link between NoV RNA replication complex formation and the pathogenesis of this virus for mice.

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Section: Discussionmentioning

confidence: 65%

mentioning

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Expression and Localization Kinetics Of The Nov Rdrp In Tranmentioning

confidence: 99%

See 3 more Smart Citations

Two Membrane-Associated Regions within the Nodamura Virus RNA-Dependent RNA Polymerase Are Critical for both Mitochondrial Localization and RNA Replication

Gant

Moreno

Varela-Ramı́rez

et al. 2014

J Virol

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A Noda-like Virus Isolated from the Sweetpotato Pest Spodoptera eridania (Cramer) (Lep.; Noctuidae)

Zeddam

Rodriguez

Ravallec

et al. 1999

Journal of Invertebrate Pathology

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Recovery of Infectivity from cDNA Clones of Nodamura Virus and Identification of Small Nonstructural Proteins

2003

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Nodamura virus (NoV) was the first isolated member of the Nodaviridae, and is the type species of the alphanodavirus genus. The alphanodaviruses infect insects; NoV is unique in that it can also lethally infect mammals. Nodaviruses have bipartite positive-sense RNA genomes in which RNA1 encodes the RNA-dependent RNA polymerase and the smaller genome segment, RNA2, encodes the capsid protein precursor. To facilitate the study of NoV, we generated infectious cDNA clones of its two genomic RNAs. Transcription of these NoV1 and NoV2 cDNAs in mammalian cells led to viral RNA replication, protein synthesis, and production of infectious virus. Subgenomic RNA3 was produced during RNA replication and encodes nonstructural proteins B1 and B2 in overlapping ORFs. Site-directed mutagenesis of these ORFs, followed by SDS-PAGE and MALDI-TOF mass spectrometry analyses, showed synthesis of B1 and two forms of B2 (B2-134 and B2-137) during viral replication. We also characterized a point mutation in RNA1 far upstream of the RNA3 region that resulted in decreased RNA3 synthesis and RNA2 replication, and a reduced yield of infectious particles. The ability to reproduce the entire life cycle of this unusual nodavirus from cDNA clones will facilitate further analysis of NoV RNA replication and pathogenesis.

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Morphogenesis of the Nodamura virus in the larvae of the lepidopteranGalleria mellonella (L.)

Cited by 23 publications

References 26 publications

Two Membrane-Associated Regions within the Nodamura Virus RNA-Dependent RNA Polymerase Are Critical for both Mitochondrial Localization and RNA Replication

Two Membrane-Associated Regions within the Nodamura Virus RNA-Dependent RNA Polymerase Are Critical for both Mitochondrial Localization and RNA Replication

A Noda-like Virus Isolated from the Sweetpotato Pest Spodoptera eridania (Cramer) (Lep.; Noctuidae)

Recovery of Infectivity from cDNA Clones of Nodamura Virus and Identification of Small Nonstructural Proteins

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