Genomic regions of neurovirulence and attenuation in Theiler murine encephalomyelitis virus.

Calenoff, Miriam A.; Faaberg, Kay S.; Lipton, Howard L.

doi:10.1073/pnas.87.3.978

Cited by 56 publications

(64 citation statements)

References 46 publications

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“…Viral persistence appears to be required to induce the chronic demyelinating disease, but the exact mechanisms involved in persistence are still poorly understood. Among the viral determinants of persistence identified, the capsid plays a crucial role, probably affecting the tropism of the virus in the CNS (2,11,22). However, viral factors allowing the virus to escape the host immune response could also play a pivotal role in establishing persistence.…”

mentioning

confidence: 99%

The Leader Protein of Theiler's Virus Inhibits Immediate-Early Alpha/Beta Interferon Production

Pesch

Eyll

Michiels

2001

J Virol

115

145

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Theiler's virus is a picornavirus responsible for a persistent infection of the central nervous system of the mouse, leading to a chronic demyelinating disease considered to be a model for multiple sclerosis. The leader (L) protein encoded by Theiler's virus is a 76-amino-acid-long peptide containing a zinc-binding motif. This motif is conserved in the L proteins of all cardioviruses, including encephalomyocarditis virus. The L protein of Theiler's virus was suggested to interfere with the alpha/beta interferon (IFN-␣/␤) response (W.-P. Kong, G. D. Ghadge, and R. P. Roos, Proc. Natl. Acad. Sci. USA 91:1796-1800, 1994). We show that expression of the L protein indeed inhibits the production of alpha/beta interferon by infected L929 cells. The L protein specifically inhibits the transcription of the IFN-␣4 and IFN-␤ genes, which are known to be activated early in response to viral infection. Mutation of the zinc finger was sufficient to block the anti-interferon activity, outlining the importance of this motif in the L protein function. In agreement with the anti-interferon role of the L protein, a virus bearing a mutation in the zinc-binding motif was dramatically impaired in its ability to persist in the central nervous system of SJL/J mice.Theiler's murine encephalomyelitis virus (TMEV) (or Theiler's virus), a member of the Picornavirus family, is a naturally occurring enteric pathogen of the mouse, responsible for central nervous system (CNS) infections (32). The neurovirulent strains (GD7 and FA) cause an acute lethal encephalomyelitis. The persistent strains (DA and BeAn) induce a biphasic disease after intracerebral inoculation of susceptible mice (18). After a mild encephalomyelitis lasting about 2 weeks, mice develop a chronic demyelinating disease, which serves as an experimental model of multiple sclerosis (for review, see references 8 and 25).TMEV can be recovered from the spinal cord white matter virtually lifelong, indicating that active viral replication occurs during persistence despite the host immune response. Viral persistence appears to be required to induce the chronic demyelinating disease, but the exact mechanisms involved in persistence are still poorly understood. Among the viral determinants of persistence identified, the capsid plays a crucial role, probably affecting the tropism of the virus in the CNS (2, 11, 22). However, viral factors allowing the virus to escape the host immune response could also play a pivotal role in establishing persistence.Antagonism of the innate immune response mediated by alpha/beta interferons (IFNs-␣/␤) is a common determinant of virulence (33). Indeed, IFNs-␣/␤ are cytokines produced by most cell types in response to viral infection. The antiviral action of IFNs is mediated by the activation of proteins, such as protein kinase R (PKR), the 2Ј-5Ј-oligodenylate synthetase, or the Mx proteins, known to interfere with the viral cycle (29).The genome of picornaviruses is translated as a long precursor polyprotein that undergoes autoproteolytic cleavage to yiel...

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confidence: 99%

The Leader Protein of Theiler's Virus Inhibits Immediate-Early Alpha/Beta Interferon Production

Pesch

Eyll

Michiels

2001

J Virol

115

145

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“…Many efforts have been taken to map a determinant for virus persistence, and it has been elucidated that the capsid that carries the host receptor recognition site and the antigenic sites is responsible for viral persistence (4,11). The capsid of TMEV shares common features of the picornaviruses, a family of small RNA viruses that have three major capsid proteins (VP1, VP2, and VP3) assembled into an icosahedral shell.…”

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Sialylation of the Host Receptor May Modulate Entry of Demyelinating Persistent Theiler's Virus

Zhou

Luo

Wu³

et al. 2000

J Virol

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Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus of the Cardiovirus genus. Certain strains of TMEV may cause a chronic demyelinating disease, which is very similar to multiple sclerosis in humans, associated with a persistent viral infection in the mouse central nervous system (CNS). Other strains of TMEV only cause an acute infection without persistence in the CNS. It has been shown that sialic acid is a receptor moiety only for the persistent TMEV strains and not for the nonpersistent strains. We report the effect of sialylation on cell surface on entry and the complex structure of DA virus, a persistent TMEV, and the receptor moiety mimic, sialyllactose, refined to a resolution of 3.0 Å. The ligand binds to a pocket on the viral surface, composed mainly of the amino acid residues from capsid protein VP2 puff B, in the vicinity of the VP1 loop and VP3 C terminus. The interaction of the receptor moiety with the persistent DA strain provides new understanding for the demyelinating persistent infection in the mouse CNS by TMEV.Theiler's murine encephalomyelitis virus (TMEV) belongs to the Cardiovirus genus of the family Picornaviridae based on sequence analysis (34). Based on the characteristics of the disease they cause, TMEV strains are divided into two groups. Viruses of one group, including strain GDVII and FA, are highly neurovirulent, causing a rapid destruction of the neuron and killing their host in a matter of days. These viruses are unable to persist and to induce demyelination in those rare survivors (22). The other group, including strains DA, BeAn, WW, TO4, and Yale, are referred to as the Theiler's original (TO) group (23). Viruses of the TO group are much less virulent than GDVII and FA and cause a biphasic disease with mild central nervous system (CNS) damage. The first phase, or early onset, is acute encephalitis that occurs during the initial few days following intracranial inoculation. At that time, the virus is also found in neurons of the gray matter in the brain and spinal cord. However, the number of infected cells is small and most of the animals survive. Soon after, the neurons are cleared of the virus and the disease enters a second phase, or late onset, during which the virus is found to be persistent in the white matter of the spinal cord. At this stage of the viral persistence, patchy inflammation and demyelination develops in the spinal cord at the sites of infection (7, 23). The symptoms of the demyelination disease of mice caused by TMEV persistence infection in the CNS resemble those of multiple sclerosis (MS), a chronic demyelinating disease of the human CNS. Among the animal models of virus-induced demyelination in the last two decades, TMEV infection has emerged as one of the best models for studying MS.Although these two groups of TMEV strains have both been shown to replicate well in BHK-21 cells and share high amino acid sequence homology (31, 34-36), they apparently display different pathogenesis characteristics in vivo. Many efforts have been taken to map ...

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“…Recombinant TMEVs, constructed by exchanging corresponding genomic regions between the highly virulent GDVII and less virulent BeAn or DA cDNAs, have been used to map a determinant for virus persistence (and demyelination) to the P1 sequences encoding the capsid proteins (Calenoff et al, 1990 ;Fu et al, 1990 ;McAllister et al, 1990 ;Rodriguez et al, 1992). However, there are conflicting results regarding whether this determinant can include GDVII sequences (Fu et al, 1990 ;Rodriguez et al, 1992 ;Adami et al, 1997).…”

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Attenuation of neurovirulence of Theiler's murine encephalomyelitis virus strain GDVII is not sufficient to establish persistence in the central nervous system.

Lipton¹,

Pritchard²,

Calenoff³

1998

Journal of General Virology

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Virus recombinants constructed from Theiler's murine encephalomyelitis virus (TMEV) strain GDVII, which causes a rapidly fatal encephalitis in mice, and the less virulent BeAn, which persists in the murine central nervous system (CNS) and causes inflammatory demyelination, and a GDVII mutant deleted of 46 of 76 leader protein amino acids were analysed for virus persistence in the CNS. The two recombinant and mutant viruses principally contain GDVII sequences including the nucleotides encoding the polyprotein and 3h untranslated region. These viruses were found to replicate in the CNS of mice but they did not produce acute encephalitis or paralysis, i.e. they were attenuated in neurovirulence compared to the GDVII parent. More important, none of the viruses persisted in the mouse CNS nor caused chronic demyelination. Thus, attenuation of GDVII neurovirulence alone is not sufficient to establish TMEV persistence. This result is discussed in the context of a genomic determinant for persistence.The Theiler's murine encephalomyelitis viruses (TMEV), members of the genus Cardiovirus in the family Picornaviridae, can be divided into two groups based on their neurovirulence characteristics after intracerebral (i.c.) inoculation of mice. Highly virulent strains, such as GDVII virus, cause a rapidly fatal encephalitis in mice. The less virulent strains, such as BeAn and DA, are characterized by at least a 10&-fold reduction in the mean 50 % lethal dose (LD &! ) compared with the virulent group and by their ability to persist in the central nervous system (CNS). TMEV persistence which leads to immuno-

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Genomic regions of neurovirulence and attenuation in Theiler murine encephalomyelitis virus.

Cited by 56 publications

References 46 publications

The Leader Protein of Theiler's Virus Inhibits Immediate-Early Alpha/Beta Interferon Production

The Leader Protein of Theiler's Virus Inhibits Immediate-Early Alpha/Beta Interferon Production

Sialylation of the Host Receptor May Modulate Entry of Demyelinating Persistent Theiler's Virus

Attenuation of neurovirulence of Theiler's murine encephalomyelitis virus strain GDVII is not sufficient to establish persistence in the central nervous system.

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