Molecular characterization of virus-specific RNA produced in the brains of flavivirus-susceptible and -resistant mice after challenge with Murray Valley encephalitis virus.

Urosevic, Nadia; Maanen, Marc-Henri van; Mansfield, J.P.; Mackenzie, John S.; Shellam, Geoffrey

doi:10.1099/0022-1317-78-1-23

Cited by 66 publications

(62 citation statements)

References 18 publications

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“…The 11-kb band corresponds to the full-length viral genomic RNA. The ϳ0.6-kb band is a genome fragment that has previously been reported to accumulate in flavivirus-infected cells and mouse brains (42,68). The ratios of the ϳ0.6-kb band to the genomic RNA were similar in RV and He extracts.…”

Section: Comparison Of Viral Rna Levels In Congenic Susceptible He Anmentioning

confidence: 76%

“…The major cleavage product detected from the 3Ј region of the WNV genome was ϳ0.6 kb in size. The accumulation of a 3Ј fragment of 521 to 523 nt in Japanese encephalitis virus (JEV)-infected BHK and C6/36 cells was previously reported (42), and an ϳ0.6-kb fragment was detected in Murray Valley encephalitis virus-infected mouse brain cells (68). Equivalent increases in the levels of the small 3Ј viral RNA fragment and the full-length genome RNA were observed in RV cells with suppressed levels of RNase L and in susceptible RNase L Ϫ/Ϫ cells.…”

Section: Discussionmentioning

confidence: 95%

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RNase L Plays a Role in the Antiviral Response to West Nile Virus

Scherbik

Paranjape

Stockman

et al. 2006

J Virol

129

140

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Alleles at the Flv locus determine disease outcome after a flavivirus infection in mice. Although comparable numbers of congenic resistant and susceptible mouse embryo fibroblasts (MEFs) are infected by the flavivirus West Nile virus (WNV), resistant MEFs produce ϳ100-to 150-fold lower titers than susceptible ones and flavivirus titers in the brains of resistant and susceptible animals can differ by >10,000-fold. The Flv locus was previously identified as the 2-5 oligoadenylate synthetase 1b (Oas1b) gene. Oas gene expression is upregulated by interferon (IFN), and after activation by double-stranded RNA, some mouse synthetases produce 2-5A, which activates latent RNase L to degrade viral and cellular RNAs. To determine whether the lower levels of intracellular flavivirus genomic RNA from resistant mice detected in cells at all times after infection were mediated by RNase L, RNase L activity levels in congenic resistant and susceptible cells were compared. Similar moderate levels of RNase L activation by transfected 2-5A were observed in both types of uninfected cells. After WNV infection, the mRNAs of IFN-␤ and three Oas genes were up-regulated to similar levels in both types of cells. However, significant levels of RNase L activity were not detected until 72 h after WNV infection and the patterns of viral RNA cleavage products generated were similar in both types of cells. When RNase L activity was down-regulated in resistant cells via stable expression of a dominant negative RNase L mutant, ϳ5-to 10-times-higher yields of WNV were produced. Similarly, about ϳ5-to 10-times-higher virus yields were produced by susceptible C57BL/6 RNase L Variation in susceptibility to flavivirus-induced disease among mice was first observed in the 1920s and subsequently shown to be controlled by a single locus (56,72). This virus-specific resistance is dominant. Studies with the C3H.PRI-Flv r and C3H/HeJ congenic pair of mouse strains (26) showed that although resistant mice support the replication of flaviviruses, virus titers in their tissues are significantly lower and the spread of infection is slower compared to that in susceptible mice (4,24,32,65). Cell cultures prepared from various tissues obtained from resistant mice also produce lower yields of flaviviruses than do comparable cell cultures from susceptible mice (13; reviewed in reference 8). Coinheritance of the Flv alleles with those of the Ric locus on chromosome 5 identified the chromosomal location of the Flv locus (36). The Flv locus was then mapped on mouse chromosome 5 by linkage analysis first with known flanking genes (61) and then with microsatellite markers (67). The Oas1b gene was identified as the Flv locus by a positional cloning strategy (51). Mashimo et al. (45) confirmed the identification of this gene. The transcript of the Oas1b allele in susceptible mice contains a premature stop codon and encodes a truncated protein. The mechanism(s) through which the products of the different Oas1b alleles confer differential susceptibility to flavivirus-induced ...

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Section: Comparison Of Viral Rna Levels In Congenic Susceptible He Anmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 95%

RNase L Plays a Role in the Antiviral Response to West Nile Virus

Scherbik

Paranjape

Stockman

et al. 2006

J Virol

129

140

View full text Add to dashboard Cite

show abstract

“…Results from previous sucrose gradient analyses (13) and recent RNase protection experiments (data not shown) indicate that the levels of genomic flavivirus RNA but not antigenomic RNA are reduced preferentially in flavivirus-infected resistant cells as compared with susceptible cells. Also, more flavivirus doublestranded RNA and less viral single-stranded RNA were detected in the brains of resistant mice as compared with those of susceptible animals (44). Because genomic RNA is found free in the cytoplasm, it would be more susceptible to digestion by RNase L than would antigenomic RNA, which is present only in double-stranded replication intermediate RNA structures.…”

Section: Discussionmentioning

confidence: 99%

Positional cloning of the murine flavivirus resistance gene

Perelygin

Scherbik

Zhulin

et al. 2002

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

247

198

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Inbred mouse strains exhibit significant differences in their susceptibility to viruses in the genus Flavivirus, which includes human pathogens such as yellow fever, Dengue, and West Nile virus. A single gene, designated Flv, confers this differential susceptibility and was mapped previously to a region of mouse chromosome 5. A positional cloning strategy was used to identify 22 genes from the Flv gene interval including 10 members of the 2 -5 -oligoadenylate synthetase gene family. One 2 -5 -oligoadenylate synthetase gene, Oas1b, was identified as Flv by correlation between genotype and phenotype in nine mouse strains. Susceptible mouse strains produce a protein lacking 30% of the C-terminal sequence as compared with the resistant counterpart because of the presence of a premature stop codon. The Oas1b gene differs from all the other murine Oas genes by a unique four-amino acid deletion in the P-loop located within the conserved RNA binding domain. Expression of the resistant allele of Oas1b in susceptible embryo fibroblasts resulted in partial inhibition of the replication of a flavivirus but not of an alpha togavirus.I nnate resistance to flavivirus-induced morbidity and mortality was demonstrated in mice in the 1920s (1) and showed monogenic autosomal dominant inheritance (2). The alleles that determined resistance and susceptibility were designated Flv r and Flv s , respectively (3). Resistant mice are susceptible to infections with other types of viruses but are resistant to all flaviviruses (4). Resistant mice can be infected by flaviviruses, but the virus titers in their tissues are lower by 1,000-10,000 times than those in the tissues of susceptible animals, and the spread of the infection in resistant mice is slower (5, 6). Cell cultures derived from many different tissues of resistant mice also produce lower yields of virus; peak titers from resistant cultures are 100-1,000 times lower than those from susceptible cultures (7-9). Previous studies indicate that the Flv gene product acts intracellularly on flavivirus replication.The flavivirus-resistant allele was demonstrated in wild Mus musculus domesticus populations in both the U.S. and Australia, and flavivirus genetic resistance was reported in other Mus species (10-12). Most commonly used inbred laboratory mouse strains were derived from a small number of progenitors, and the majority of them have a homozygous flavivirus-susceptible genotype. Only the Det, BSVR, BRVR, CASA͞Rk, CAST͞Ei, MOLD͞Rk, and PRI inbred strains have the resistant allele (13). The characteristics of a resistant-like allele (designated Flv r -like) in CASA͞Rk and CAST͞Ei strains were similar to those of the PRI Flv r allele. The MOLD͞Rk animals carry an allele designated minor resistance, Flv mr , that can protect carriers from disease after infection with the attenuated 17D strain of yellow fever virus but not from the virulent Murray Valley encephalitis virus (10).The resistant allele from donor PRI mice was introduced onto the susceptible C3H͞He background to produce the co...

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“…Flv controls susceptibility to neurotropic flaviviruses in mice, and it is known that the protection conferred by Flv r , the resistant allele at the Flv locus, correlates with the restriction of virus replication in the CNS (12)(13)(14)(15). We were therefore interested in determining whether the WN virus replicates differently within the CNS of susceptible and resistant strains.…”

Section: Resultsmentioning

confidence: 99%

A nonsense mutation in the gene encoding 2′-5′-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice

Mashimo

Lucas²,

Simon-Chazottes³

et al. 2002

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

256

215

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A mouse model has been established to investigate the genetic determinism of host susceptibility to West Nile (WN) virus, a member of the genus flavivirus and family Flaviviridae. Whereas WN virus causes encephalitis and death in most laboratory inbred mouse strains after peripheral inoculation, most strains derived from recently trapped wild mice are completely resistant. The phenotype of resistance͞susceptibility is determined by a major locus, Wnv, mapping to chromosome 5 within the 0.4-cM-wide interval defined by markers D5Mit408 and D5Mit242. We constructed a high resolution composite͞consensus map of the interval by merging the data from the mouse T31 Radiation Hybrid map and those from the homologous region of human chromosome 12q, and found the cluster of genes encoding 2 -5 -oligoadenylate synthetases (2 -5 -OAS) to be the most prominent candidate. This cluster encodes a multimember family of IFN-inducible proteins that is known to play an important role in the established endogenous antiviral pathway. Comparing the cDNA sequences of 2 -5 -OAS L1, L2, and L3 isoforms, between susceptible and resistant strains, we identified a STOP codon in exon 4 of the gene encoding the L1 isoform in susceptible strains that can lead to a truncated form with amputation of one domain, whereas all resistant mice tested so far have a normal copy of this gene. The observation that WN virus sensitivity of susceptible mice was completely correlated with the occurrence of a point mutation in 2 -5 -OAS L1 suggests that this isoform may play a critical role in WN pathogenesis.F lavivirus is a genus of the Flaviviridae family that comprises over 70 positive-sense, single-stranded, and enveloped RNA viruses, most of which are arthropod-borne (1). Mosquito-borne flaviviruses such as dengue (DEN), Japanese encephalitis (JE), yellow fever (YF), and West Nile (WN) viruses can cause epidemic outbreaks in humans, and patients infected may exhibit a wide range of acute diseases, from nonspecific febrile illness to severe hemorrhagic manifestations (DEN and YF) or encephalitic syndromes (JE and WN), sometimes associated with a high (up to 50%) fatality rate. The reasons why flaviviruses cause clinical manifestations only in a small percentage of infected individuals have not yet been clearly elucidated but are supposed to involve host-dependent genetic factors.Over the past 5 years, WN fever has been an emerging concern for public health in Europe, in the Middle East, and more recently in the United States. In Israel and the United States, where the Isr98͞NY99 variant of WN virus was frequently isolated during recent outbreaks, approximately 20% of infected persons developed febrile illness, with a high rate of mortality among patients with neurological symptoms (2, 3). This result suggests that susceptibility and sensitivity to WN virus infections might depend, at least in part, on host genetic factors (4). In the present study we investigated the influence of the host genetic constitution on the severity of WN virus infection, by using...

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Molecular characterization of virus-specific RNA produced in the brains of flavivirus-susceptible and -resistant mice after challenge with Murray Valley encephalitis virus.

Cited by 66 publications

References 18 publications

RNase L Plays a Role in the Antiviral Response to West Nile Virus

RNase L Plays a Role in the Antiviral Response to West Nile Virus

Positional cloning of the murine flavivirus resistance gene

A nonsense mutation in the gene encoding 2′-5′-oligoadenylate synthetase/L1 isoform is associated with West Nile virus susceptibility in laboratory mice

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