Neurovirulence determinants of genetically engineered Theiler viruses.

Fu, Jianlin; Stein, Steven; Rosenstein, Laurie; Bodwell, T; Routbort, Mark; Semler, Bert L.; Roos, Raymond P.

doi:10.1073/pnas.87.11.4125

Cited by 69 publications

(82 citation statements)

References 26 publications

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“…It will be of interest if the GDVII apoptotic protein is found to be a capsid protein, since this region of GDVII has been found to be critical for neurovirulence (11).…”

Section: Discussionmentioning

confidence: 99%

“…Do the differences in apoptotic activities of DA versus GDVII play a role in TMEV subgroup-specific CNS disease phenotypes? GDVII virus is thought to kill mice because of neurovirulent determinants in capsid proteins (11), allowing the virus to quickly replicate to high titers in the CNS; in addition, the block in type I IFN production by GDVII L will interfere with virus clearance (23). In the case of DA virus infection, apoptotic activity induced by this slowergrowing virus may limit replication; in addition, the block in type I IFN production may foster virus persistence.…”

Section: Discussionmentioning

confidence: 99%

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Apoptotic and Antiapoptotic Activity of L Protein of Theiler's Murine Encephalomyelitis Virus

Stavrou¹,

Ghadge²

2011

J Virol

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Viruses frequently have genes with proapoptotic or antiapoptotic activity that may vary in different cell types. The apoptosis that is induced can trigger either a protective or destructive immune response, thereby facilitating virus clearance or persistence of the virus. Apoptotic and antiapoptotic genes have been identified in a number of picornaviruses (reviewed in reference 1). Genes regulating apoptosis in Theiler's murine encephalomyelitis virus (TMEV) have been of special interest because of their potential importance in the pathogenesis of TMEV-induced diseases (reviewed in reference 16).TMEV is a member of the Theilovirus species of the Cardiovirus genus of the Picornaviridae; the Cardiovirus genus also includes the Encephalomyocarditis virus (EMCV) species, which comprises EMCV and mengovirus. TMEV strains can be divided into two subgroups on the basis of their differing biological properties. The GDVII strain and other members of the GDVII subgroup of TMEV are highly virulent and produce a fatal, acute polioencephalomyelitis in mice with no persistence of the virus. In contrast, DA, BeAn, and other members of the less-virulent TO subgroup induce an early transient subclinical neuronal disease followed by a chronic progressive inflammatory demyelination, TMEV-induced demyelinating disease (TMEV-IDD), with persistence of the virus in the central nervous system (CNS) for the life of the mouse. During TMEV-IDD, relatively large amounts of the TMEV genome persist in oligodendrocytes and microglia, with low levels of infectious virus and viral antigen, i.e., there is a restricted expression of DA viral proteins. TMEV-IDD serves as a model of multiple sclerosis because of the similarity in the demyelinating pathology and because the immune system appears to contribute to pathology in both disorders. The remarkable disease phenotype of TO subgroup strains has made TMEV a subject of continuing interest.Apoptosis has been described during early infection of mice with strains from both subgroups of TMEV and during the late TMEV-IDD. During TMEV-IDD, apoptosis of T cells, microglia/macrophages, and oligodendrocytes has been described (2,5,20,26). In vitro studies have implicated the cardiovirus L protein, which is encoded between the start of the polyprotein and the P1 capsid proteins (Fig. 1), in regulating apoptosis. In vitro studies of TMEV carried out by Fan et al. (9) showed that transfection of an expression construct of BeAn L into BHK-21 cells and a mouse macrophage cell line led to cell death and apoptosis, while Romanova et al. (18) found that L of other cardioviruses has antiapoptotic activity, since infection with a mengovirus with a mutation in the L zinc-binding domain led to apoptosis of HeLa cells that was not seen following wild-type (wt) mengovirus infection. In order to clarify the latter observations and further characterize the apoptotic activity of TMEV, we investigated apoptosis in different cell types following transfection of DA and GDVII L expression constructs and following infection ...

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“…It will be of interest if the GDVII apoptotic protein is found to be a capsid protein, since this region of GDVII has been found to be critical for neurovirulence (11).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Apoptotic and Antiapoptotic Activity of L Protein of Theiler's Murine Encephalomyelitis Virus

Stavrou¹,

Ghadge²

2011

J Virol

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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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confidence: 99%

“…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). Persistence of GDVII virus is difficult to assess directly because few or no infected animals survive at low inoculation doses, e.g.…”

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confidence: 99%

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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“…The analysis of the sequence comparison between NIHE and the other TMEV sequences demonstrates clusters of differences in the amino acid sequence (9,12,17,26,32,40,41,45). Although we present clear evidence that NIHE is neurovirulent, we were surprised to observe the number of instances in which the NIHE sequence segregated with the persistent strains.…”

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confidence: 97%

Identification of a Novel Neuropathogenic Theiler's Murine Encephalomyelitis Virus

Buckwalter

Nga

Gouilh

et al. 2011

J Virol

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Theiler's murine encephalitis viruses (TMEV) are divided into two subgroups based on their neurovirulence. Persistent strains resemble Theiler's original viruses (referred to as the TO subgroup), which largely induce a subclinical polioencephalomyelitis during the acute phase of the disease and can persist in the spinal cord of susceptible animals, inducing a chronic demyelinating disease. In contrast, members of the neurovirulent subgroup cause an acute encephalitis characterized by the rapid onset of paralysis and death within days following intracranial inoculation. We report herein the characterization of a novel neurovirulent strain of TMEV, identified using pyrosequencing technology and referred to as NIHE. Complete coverage of the NIHE viral genome was obtained, and it shares <90% nucleotide sequence identity to known TMEV strains irrespective of subgroup, with the greatest sequence variability being observed in genes encoding the leader and capsid proteins. The histopathological analysis of infected brain and spinal cord demonstrate inflammatory lesions and neuronal necrosis during acute infection with no evidence of viral persistence or chronic disease. Intriguingly, genetic analysis indicates the putative expression of the L* protein, considered a hallmark of strains within the persistent subgroup. Thus, the identification and characterization of a novel neurovirulent TMEV strain sharing features previously associated with both subgroups will lead to a deeper understanding of the evolution of TMEV strains and new insights into the determinants of neurovirulence.Theilioviruses have positive-sense, single-stranded RNA genomes and are members of the Picornaviridae family and the Cardiovirus genus. Several serotypes have been identified, causing disease in rodents, such as Theiler's murine encephalomyelitis virus (TMEV) (36, 37) and rat Theiler-like virus (RTV) (28), and humans, such as Vilyuisk human encephalomyelititis virus (VHEV) (6) and Saffold viruses (7,13,44). TMEV is an enteric pathogen that follows the fecal-oral route of infection; however, when inoculated intracranialy (IC), it can cause severe pathology in susceptible mouse strains. As a natural mouse pathogen, TMEV provides a valuable experimental model for understanding host-pathogen interactions. The TMEV serotype is divided into two subgroups based on the pathogenesis of the disease. Members of the TO subgroup, so named because they resemble Theiler's original strains (36), cause a biphasic infection. The early phase is an acute poliomyelitis characterized by viral replication in the neurons of the brain (1, 18). During the late phase of infection, the virus progresses from the gray to the white matter of the spinal cord, where, depending on the genetics of the mouse strain (4), it can persist for the life of the animal within various cell types (2, 21), causing in some instances chronic demyelination (19). In contrast, the second subgroup, consisting of the GDVII and FA strains, are neurovirulent, and their pathology is characterized by a...

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Neurovirulence determinants of genetically engineered Theiler viruses.

Cited by 69 publications

References 26 publications

Apoptotic and Antiapoptotic Activity of L Protein of Theiler's Murine Encephalomyelitis Virus

Apoptotic and Antiapoptotic Activity of L Protein of Theiler's Murine Encephalomyelitis Virus

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

Identification of a Novel Neuropathogenic Theiler's Murine Encephalomyelitis Virus

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