Functional Analysis of RNA Structures Present at the 3′ Extremity of the Murine Norovirus Genome: the Variable Polypyrimidine Tract Plays a Role in Viral Virulence

Bailey, Dalan; Karakasiliotis, Ioannis; Vashist, Surender; Chung, Liliane; Reese, Jivan; McFadden, Nora; Benson, Alicia; Yarovinsky, Felix; Simmonds, Peter; Goodfellow, Ian

doi:10.1128/jvi.02053-09

Cited by 55 publications

(45 citation statements)

References 48 publications

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“…Although no differences in replicative fitness was observed in cell culture, previous characterization of MNV mutants that were non-attenuated in cell culture demonstrated significant replicative defects in a whole animal model (34,41). To investigate whether the effect of RNA structure disruption was similarly only manifested in vivo , we inoculated immune competent C57BL/6 mice with three challenge doses (10, 100 or 1000 TCID 50 ) of WT, F1, F2 and F1/F2 mutant viruses and assayed faecal samples for MNV RNA initially for a month post-infection (inoculation A) and in a repeat inoculation (B) at time points (days 1, 3 and 5) to quantify replication in the gastrointestinal tract.…”

Section: Resultsmentioning

confidence: 71%

Influence of genome-scale RNA structure disruption on the replication of murine norovirus—similar replication kinetics in cell culture but attenuation of viral fitness in vivo

McFadden

Arias

Dry

et al. 2013

Nucleic Acids Research

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Mechanisms by which certain RNA viruses, such as hepatitis C virus, establish persistent infections and cause chronic disease are of fundamental importance in viral pathogenesis. Mammalian positive-stranded RNA viruses establishing persistence typically possess genome-scale ordered RNA secondary structure (GORS) in their genomes. Murine norovirus (MNV) persists in immunocompetent mice and provides an experimental model to functionally characterize GORS. Substitution mutants were constructed with coding sequences in NS3/4- and NS6/7-coding regions replaced with sequences with identical coding and (di-)nucleotide composition but disrupted RNA secondary structure (F1, F2, F1/F2 mutants). Mutants replicated with similar kinetics to wild-type (WT) MNV3 in RAW264.7 cells and primary macrophages, exhibited similar (highly restricted) induction and susceptibility to interferon-coupled cellular responses and equal replication fitness by serial passaging of co-cultures. In vivo, both WT and F1/F2 mutant viruses persistently infected mice, although F1, F2 and F1/F2 mutant viruses were rapidly eliminated 1–7 days post-inoculation in competition experiments with WT. F1/F2 mutants recovered from tissues at 9 months showed higher synonymous substitution rates than WT and nucleotide substitutions that potentially restored of RNA secondary structure. GORS plays no role in basic replication of MNV but potentially contributes to viral fitness and persistence in vivo.

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Section: Resultsmentioning

confidence: 71%

Influence of genome-scale RNA structure disruption on the replication of murine norovirus—similar replication kinetics in cell culture but attenuation of viral fitness in vivo

McFadden

Arias

Dry

et al. 2013

Nucleic Acids Research

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“…Evidence indicates that RNA structures in the NoV genome also regulate viral virulence. A polypyrimidine (pY) tract within a conserved stem-loop in the 3′ untranslated region of the MuNoV-1 genome, which binds cellular poly(rC) binding protein and polypyrimidine tract binding protein, is not required for virus replication in vitro , but its removal results in a partially attenuated virus in STAT1 -/- mice (Bailey et al, 2010). Similarly, secondary structure elements in NS3/4 and NS6/7 of MuNoV-3 enhance viral fitness, although they are not required for replication in vitro or persistence establishment in immunocompetent mice (McFadden et al, 2013).…”

Section: Elucidating Norovirus Pathogenesis In Animal Modelsmentioning

confidence: 99%

Advances in Norovirus Biology

Karst

Wobus

Goodfellow

et al. 2014

Cell Host & Microbe

189

208

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Human noroviruses are a major cause of epidemic and sporadic gastroenteritis worldwide, and can chronically infect immunocompromised patients. Efforts to develop effective vaccines and antivirals have been hindered by the uncultivable nature and extreme genetic diversity of human noroviruses. Although they remain a particularly challenging pathogen to study, recent advances in norovirus animal models and in vitro cultivation systems have led to an increased understanding of norovirus molecular biology and replication, pathogenesis, cell tropism, and innate and adaptive immunity. Furthermore, clinical trials of vaccines consisting of nonreplicating virus-like particles have shown promise. In this review, we summarize these recent advances and discuss controversies in the field, which is rapidly progressing towards generation of antiviral agents and increasingly effective vaccines.

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“…The substitution of a C for a T at nucleotide 8115 converted a stop codon (TAG) to a glutamine codon (CAG) resulting in a five codon-extension of the ORF3 compared to other VESV-related vesiviruses (data not shown). The 3’-end of the calicivirus RNA genome has been shown to play a crucial role in the initiation of virus replication [31,32]. Nevertheless, modifications introduced into the genomes of feline calicivirus and murine norovirus showed that this region could tolerate a number of sequence changes while supporting virus replication [30,32].…”

Section: Resultsmentioning

confidence: 99%

Genetic characterization of a reptilian calicivirus (Cro1)

Sandoval-Jaime¹,

Parra²,

Smith

et al. 2012

Virol J

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BackgroundVesiviruses in the family Caliciviridae infect a broad range of animal hosts including mammals, birds, fish, amphibians and reptiles. The vesivirus Cro1 strains were isolated from diseased snakes in the San Diego zoo in 1978 and reported as the first caliciviruses found in reptiles. The goal of this study was to characterize the Cro1 strain 780032I that was isolated in cell culture from a rock rattlesnake (Crotalus lepidus) in the original outbreak.ResultsWe re-amplified the original virus stock in Vero cells, and determined its full-length genome sequence. The Cro1 genome is 8296 nucleotides (nt) in length and has a typical vesivirus organization, with three open reading frames (ORF), ORF1 (5643 nt), ORF2 (2121 nt), and ORF3 (348 nt) encoding a nonstructural polyprotein, the major capsid protein precursor, and a minor structural protein, respectively. Phylogenetic analysis of the full-length genome sequence revealed that the Cro1 virus clustered most closely with the VESV species of the genus Vesivirus, but was genetically distinct (82-83% identities with closest strains).ConclusionsThis is the first description of a full-length genome sequence from a reptile calicivirus (Cro1). The availability of the Cro1 genome sequence should facilitate investigation of the molecular mechanisms involved in Cro1 virus evolution and host range.

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Functional Analysis of RNA Structures Present at the 3′ Extremity of the Murine Norovirus Genome: the Variable Polypyrimidine Tract Plays a Role in Viral Virulence

Cited by 55 publications

References 48 publications

Influence of genome-scale RNA structure disruption on the replication of murine norovirus—similar replication kinetics in cell culture but attenuation of viral fitness in vivo

Influence of genome-scale RNA structure disruption on the replication of murine norovirus—similar replication kinetics in cell culture but attenuation of viral fitness in vivo

Advances in Norovirus Biology

Genetic characterization of a reptilian calicivirus (Cro1)

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