A Highly Structured, Nuclease-Resistant, Noncoding RNA Produced by Flaviviruses Is Required for Pathogenicity

Pijlman, Gorben P.; Funk, Anneke; Kondratieva, Natasha; Leung, Jason Y.; Torres, Shessy; Aa, Lieke van der; Liu, Wen Jun; Palmenberg, Ann C.; Shi, Pei Yong; Hall, Roy A.; Khromykh, Alexander A.

doi:10.1016/j.chom.2008.10.007

Cited by 434 publications

(791 citation statements)

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“…Also of importance is that, at some point, an ancestral flavivirus genome must have "fragmented" to produce the individual NS3-and NS5-like "segments" present in JMTV. This is obviously a highly unusual process, as flaviviruses are transcribed as a single mRNA and subgenomic RNAs are only generated from noncoding regions (13), although functional and defective capsid proteins of dengue virus have been observed to cocirculate in nature (14,15). Unfortunately, determining exactly how the flavivirus genome formed the individual segments subsequently observed in JMTV is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 94%

A tick-borne segmented RNA virus contains genome segments derived from unsegmented viral ancestors

Qin

Shī

Tian

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

184

336

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Although segmented and unsegmented RNA viruses are commonplace, the evolutionary links between these two very different forms of genome organization are unclear. We report the discovery and characterization of a tick-borne virus-Jingmen tick virus (JMTV)-that reveals an unexpected connection between segmented and unsegmented RNA viruses. The JMTV genome comprises four segments, two of which are related to the nonstructural protein genes of the genus Flavivirus (family Flaviviridae), whereas the remaining segments are unique to this virus, have no known homologs, and contain a number of features indicative of structural protein genes. Remarkably, homology searching revealed that sequences related to JMTV were present in the cDNA library from Toxocara canis (dog roundworm; Nematoda), and that shared strong sequence and structural resemblances. Epidemiological studies showed that JMTV is distributed in tick populations across China, especially Rhipicephalus and Haemaphysalis spp., and experiences frequent host-switching and genomic reassortment. To our knowledge, JMTV is the first example of a segmented RNA virus with a genome derived in part from unsegmented viral ancestors.evolution | segmentation S egmentation is a common form of genome organization in RNA viruses, although why it has evolved more than once and is maintained in such a diverse array of viruses, including those with both positive-and negative-sense genomes, are unclear (1). Segmented and unsegmented viruses usually belong to different viral families, such that the sequence divergence between them is often too great for any meaningful evolutionary inference. The only example of "recent" genome fragmentation in a single RNA molecule occurred in a laboratory strain of foot-and-mouth disease virus (2, 3), although that this occurred following extensive propagation in cell culture means that its relationship to segmentation in nature is uncertain. Hence, the evolutionary links between unsegmented and segmented viruses, as well as the mechanisms that underpin their genesis, are poorly understood.The Flaviviridae are a family of unsegmented positive sense RNA viruses that infect vertebrate and invertebrate species, including the important human pathogens dengue virus, yellow fever virus, and hepatitis C virus. Despite the substantial sequence divergence between the Flavivirus, Pestivirus, and Hepacivirus genera that make up the Flaviviridae, they exhibit a similar genomic structure characterized by a single ORF with distinct clusters of structural and nonstructural genes. The ORF is translated into a single polyprotein, which is subsequently cleaved by cellular and viral proteases into structural and nonstructural proteins. Among the nonstructural protein products, NS3 and NS5 possess the enzymatic domains essential for RNA capping and genome replication (4), whereas the NS3 and NS2b proteins form a two-component serine protease involved in posttranslational cleavage of the viral polyprotein (5).Herein we describe the discovery and characterization of an...

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Section: Discussionmentioning

confidence: 94%

A tick-borne segmented RNA virus contains genome segments derived from unsegmented viral ancestors

Qin

Shī

Tian

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

184

336

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“…Abrogation of the formation of sfRNA through mutagenesis of the West Nile virus 3′ UTR promoted a reduction in murine neuroinvasive phenotypes [130].…”

Section: Viral Determinants Of Flavivirus Encephalitismentioning

confidence: 99%

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

2012

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Members of the genus Flavivirus are responsible for a spectrum of important neurological syndromes in humans and animals. Rodent models have been used extensively to model flavivirus neurological disease, to discover host-pathogen interactions that influence disease outcome, and as surrogates to determine the efficacy and safety of vaccines and therapeutics. In this review, we discuss the current understanding of flavivirus neuroinvasive disease and outline the host, viral and experimental factors that influence the outcome and reliability of virus infection of smallanimal models.

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“…Par exemple, les cellules infectées par le virus de l'hépatite B (VHB) sécrètent de larges quantités de particules non infectieuses, dont la protéine virale antigène de surface (HBsAg), mais sont dépourvues de capside et de génome viral [1]. Par ailleurs, des virus défec-tifs interférents, composés de génomes viraux tronqués, sont produits dans un large spectre d'infections comme la grippe et certaines infections par flavivirus [2,3]. Ces génomes tronqués, générés probablement à la suite d'erreurs de la polymérase virale ou par digestion nucléotidique partielle, sont aussi efficacement encapsidés et sécrétés que le génome viral entier [3].…”

Section: Diversité Des Particules Virales Produites Par Les Cellules unclassified

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2013

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A Highly Structured, Nuclease-Resistant, Noncoding RNA Produced by Flaviviruses Is Required for Pathogenicity

Cited by 434 publications

References 47 publications

A tick-borne segmented RNA virus contains genome segments derived from unsegmented viral ancestors

A tick-borne segmented RNA virus contains genome segments derived from unsegmented viral ancestors

The contribution of rodent models to the pathological assessment of flaviviral infections of the central nervous system

Les exosomes

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