Molecular differences between wild-type Japanese encephalitis virus strains of high and low mouse neuroinvasiveness

Ni, Haolin; Barrett, Alan D.T.

doi:10.1099/0022-1317-77-7-1449

Cited by 72 publications

(39 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This level of viremia is typical of that generated by attenuated virus strains in other rodent models of flavivirus neuropathogenesis (40,44,58). The presence and magnitude of viremia has generally been regarded as an important factor for neuroinvasion (19,41), but the consequences of a given level may depend to some extent on the host immune response to circulating virus or the associated virus burden in the peripheral tissues of infected animals.…”

Section: Discussionmentioning

confidence: 92%

Neuroadapted Yellow Fever Virus 17D: Genetic and Biological Characterization of a Highly Mouse-Neurovirulent Virus and Its Infectious Molecular Clone

Chambers

Nickells

2001

J Virol

View full text Add to dashboard Cite

A neuroadapted strain of yellow fever virus (YFV) 17D derived from a multiply mouse brain-passaged virus (Porterfield YF17D) was additionally passaged in SCID and normal mice. The virulence properties of this virus (SPYF) could be distinguished from nonneuroadapted virus (YF5.2iv, 17D infectious clone) by decreased average survival time in SCID mice after peripheral inoculation, decreased average survival time in normal adult mice after intracerebral inoculation, and occurrence of neuroinvasiveness in normal mice. SPYF exhibited more efficient growth in peripheral tissues of SCID mice than YF5.2iv, resulting in a more rapid accumulation of virus burden, but with low-titer viremia, at the time of fatal encephalitis. In cell culture, SPYF was less efficient in replication than YF5.2iv in all cell lines tested. The complete nucleotide sequence of SPYF revealed 29 nucleotide substitutions relative to YF5.2iv, and these were distributed throughout the genome. There were a total of 13 predicted amino acid substitutions, some of which correspond to known differences among the Asibi, French viscerotropic virus, French neurotropic vaccine, and YF17D vaccine strains. The envelope (E) protein contained five substitutions, within all three functional domains. Substitutions were also present in regions encoding the NS1, NS2A, NS4A, and NS5 proteins and in the 3 untranslated region (UTR). Construction of YFV harboring all of the identified coding nucleotide substitutions and those in the 3 UTR yielded a virus whose cell culture and pathogenic properties, particularly neurovirulence and neuroinvasiveness for SCID mice, generally resembled those of the original SPYF isolate. These findings implicate the E protein and possibly other regions of the genome as virulence determinants during pathogenesis of neuroadapted YF17D virus in mice. The determinants affect replication efficiency in both neural and extraneural tissues of the mouse and confer some limited host-range differences in cultured cells of nonmurine origin.Viruses within the Flavivirus genus of the family Flaviviridae are generally neurotropic, exhibiting various degrees of neurovirulence in rodent and primate hosts (41). Introduction of virus into the murine central nervous system (CNS) causes an acute encephalitis, the outcome of which can be influenced by the dose of virus and the age and strain of the mouse (15). Different strains of yellow fever virus (YFV) can be distinguished by their level of mouse neurovirulence (5,15,28,(52)(53)(54), and this property can be enhanced by serial passage of the virus in mouse brain (37,56,59). This neuroadaptation has also been observed with other flaviviruses (7,11,25). Genetic analyses of viruses which differ in their virulence properties have commonly focused on the envelope (E) protein, for which a variety of mutations have been shown to modulate neurovirulence (reviewed in reference 36). Regarding YFV, nucleotide sequence analysis of the partially attenuated French neurotropic virus (FNV) strain of YFV which was derived by ...

show abstract

Section: Discussionmentioning

confidence: 92%

Neuroadapted Yellow Fever Virus 17D: Genetic and Biological Characterization of a Highly Mouse-Neurovirulent Virus and Its Infectious Molecular Clone

Chambers

Nickells

2001

J Virol

View full text Add to dashboard Cite

show abstract

“…The 2KNS4B protein from WNV has been demonstrated to prevent STAT1 phosphorylation in IFN-treated cells (26,37). To compare the impact of NS5 and 2KNS4B from virulent and attenuated strains of these viruses on STAT1 activation, we examined phosphorylation and nuclear localization of STAT1 (pY-STAT1) by immunofluorescence assay (IFA) in IFN-treated cells expressing NS5 or 2KNS4B derived from WNV-NY99 and KUN or the virulent JEV Nakayama strain (JEV-N) (8,39) and the live attenuated vaccine strain, JEV-SA14-14-2 (JEV-SA) (40, 42) (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

The NS5 Protein of the Virulent West Nile Virus NY99 Strain Is a Potent Antagonist of Type I Interferon-Mediated JAK-STAT Signaling

Laurent-Rolle¹,

Boer²,

Lubick³

et al. 2010

J Virol

202

208

View full text Add to dashboard Cite

“…Studies of neurovirulent WNV strains and other neurovirulent flaviviruses suggest that the WNV envelope (E) and capsid (C) proteins play important roles in neuropathogenesis (3,5,33,43,44). Direct evidence for neuropathogenic contributions exists only for the WNV capsid protein since it affects the survival of neuronal cells by inducing apoptosis (66).…”

mentioning

confidence: 99%

West Nile Virus-Induced Neuroinflammation: Glial Infection and Capsid Protein-Mediated Neurovirulence

Marle¹,

Antony

Ostermann

et al. 2007

J Virol

103

110

View full text Add to dashboard Cite

West Nile virus (WNV) infection causes neurological disease at all levels of the neural axis, accompanied by neuroinflammation and neuronal loss, although the underlying mechanisms remain uncertain. Given the substantial activation of neuroinflammatory pathways observed in WNV infection, we hypothesized that WNV-mediated neuroinflammation and cell death occurred through WNV infection of both glia and neurons, which was driven in part by WNV capsid protein expression. Analysis of autopsied neural tissues from humans with WNV encephalomyelitis (WNVE) revealed WNV infection of both neurons and glia. Upregulation of proinflammatory genes, CXCL10, interleukin-1␤, and indolamine-2,3-deoxygenase with concurrent suppression of the protective astrocytespecific endoplasmic reticulum stress sensor gene, OASIS (for old astrocyte specifically induced substance), was evident in WNVE patients compared to non-WNVE controls. These findings were supported by increased ex vivo expression of these proinflammatory genes in glia infected by WNV-NY99. WNV infection caused endoplasmic reticulum stress gene induction and apoptosis in neurons but did not affect glial viability. WNV-infected astrocytic cells secreted cytotoxic factors, which caused neuronal apoptosis. The expression of the WNV-NY99 capsid protein in neurons and glia by a Sindbis virus-derived vector (SINrep5-WNVc) caused neuronal death and the release of neurotoxic factors by infected astrocytes, coupled with proinflammatory gene induction and suppression of OASIS. Striatal implantation of SINrep5-WNV C induced neuroinflammation in rats, together with the induction of CXCL10 and diminished OASIS expression, compared to controls. Moreover, magnetic resonance neuroimaging showed edema and tissue injury in the vicinity of the SINrep5-WNVc implantation site compared to controls, which was complemented by neurobehavioral abnormalities in the SINrep5-WNVc-implanted animals. These studies underscore the important interactions between the WNV capsid protein and neuroinflammation in the pathogenesis of WNV-induced neurological disorders.In North America, widespread West Nile virus (WNV) infection was first recognized in 1999 during an outbreak of viral encephalitis in New York City (32). Infection by WNV causes a spectrum of neurological disorders and ensuing death in a subset of infected individuals (24,26). WNV belongs to the flavivirus family (reviewed in references 11, 14, and 34), which are enveloped viruses with a genome consisting of one 10-to 11-kb single-stranded RNA molecule of positive-strand mRNA polarity. WNV genomic RNA contains one large open reading frame, which is translated into a single polypeptide and cleaved by viral and cellular proteases into three structural proteins and several nonstructural (NS) proteins (11, 34). The WNV structural proteins include the capsid (C) protein, the small transmembrane protein (M and its precursor preM), and the surface or envelope glycoprotein (E), which are all involved in pathogenesis. It is clear that infection of the centr...

show abstract

Molecular differences between wild-type Japanese encephalitis virus strains of high and low mouse neuroinvasiveness

Cited by 72 publications

References 12 publications

Neuroadapted Yellow Fever Virus 17D: Genetic and Biological Characterization of a Highly Mouse-Neurovirulent Virus and Its Infectious Molecular Clone

Neuroadapted Yellow Fever Virus 17D: Genetic and Biological Characterization of a Highly Mouse-Neurovirulent Virus and Its Infectious Molecular Clone

The NS5 Protein of the Virulent West Nile Virus NY99 Strain Is a Potent Antagonist of Type I Interferon-Mediated JAK-STAT Signaling

West Nile Virus-Induced Neuroinflammation: Glial Infection and Capsid Protein-Mediated Neurovirulence

Contact Info

Product

Resources

About