Pathogenesis of Theiler’s murine encephalomyelitis virus‐induced disease

The highly virulent GDVII strain of Theiler's murine encephalomyelitis virus causes acute and fatal encephalomyelitis, whereas the DA strain causes mild encephalomyelitis followed by a chronic inflammatory demyelinating disease with virus persistence. The differences in the amino acid sequences of the leader protein Theiler's murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus of the family Picornaviridae, and its strains are divided into two subgroups on the basis of their different biological activities. The neurovirulent strains, such as GDVII and FA, produce acute and fatal encephalomyelitis in mice. The persistent strains, such as TO, DA, BeAn, etc., induce mild and nonfatal encephalomyelitis, followed by a chronic demyelinating disease with virus persistence in the spinal cords of mice. This late demyelinating disease is thought to be an excellent experimental model for the human demyelinating disease multiple sclerosis (MS) (5,17,20).The TMEV genome is a single-stranded RNA molecule and translated as a long precursor polyprotein to yield 12 viral proteins by autoproteolytic cleavage (23). Two subgroup strains of TMEV have a sequence identity of approximately 95% at the amino acid level. The amino acid sequences of the proteins encoded by the P1, P2, and P3 regions of both strains are highly conserved and show 94, 96, and 98% identity, respectively. The genome has another coding region, designated the leader (L), at the most amino-terminal location of the precursor polyprotein. The L coding region encodes 76 amino acids (aa) and shows a low sequence identity of only 85% to the above-described three regions (16,19,22). Therefore, L has the greatest difference in amino acid sequence among any of the viral proteins and may play an important role in subgroupspecific biological activities of TMEV. In this study, we have investigated the subcellular localization of the L proteins of GDVII and DA strains and characterized the functional domains involved in the differential distribution between DA L and GDVII L in BHK-21 cells by a series of deletion mutant and chimeric construct experiments. MATERIALS AND METHODSPlasmid constructs. L is organized into the three domains: (i) the N-terminal atypical zinc finger domain, (ii) the acidic domain, and (iii) the serine/threonine (S/T)-rich domain. The amino acid sequence alignment of both strains is shown in Fig. 1A. Amino acid sequences of the zinc finger and acidic domains of both strains are identical. In contrast, the S/T-rich domain was less conserved. Five out of 13 residues are different. The C-terminal region consisting of 13 aa also contains three different amino acid residues between the strains. Wild-type L (Lwt) and mutated constructs of the DA or GDVII strain are depicted in Fig. 1B. Those cDNAs were generated by PCR amplification using pDAFL3 containing the full-length DA cDNA (24) or pGDVIIFL2 containing the full-length GDVII cDNA (10). L⌬Z, L⌬A, L⌬S/T, and L⌬C lack the zinc finger domain (aa 3 to 14), the acidic domain (aa 30 to 46), th...

Section: Discussionmentioning

confidence: 99%

“…The TMEV genome is a single-stranded RNA molecule and translated as a long precursor polyprotein to yield 12 viral proteins by autoproteolytic cleavage (23). Two subgroup strains of TMEV have a sequence identity of approximately 95% at the amino acid level.…”

mentioning

confidence: 99%

Different Subcellular Localization of Theiler's Murine Encephalomyelitis Virus Leader Proteins of GDVII and DA Strains in BHK-21 Cells

Taniura

Saito

Okuwa

et al. 2009

“…Infected mice show progressive flaccid paralysis, and almost all infected mice die within 2 weeks. Neither virus persistence nor demyelination is observed in the few surviving mice (4,29,54). On the other hand, TO subgroup strains cause a milder encephalomyelitis 1 to 2 weeks postinoculation (p.i.).…”

Section: Safv-related Virusesmentioning

confidence: 99%

“…The capsid proteins, especially VP1 and VP2, were found important for some of the biological activities (29). In addition to these structural proteins, the two nonstructural viral proteins, L and L*, play an important role in TMEV disease pathogenesis (4,29,54).…”

Section: Safv-related Virusesmentioning

confidence: 99%

Saffold Virus, a Novel Human Cardiovirus with Unknown Pathogenicity

Himeda

Ohara

2012

Although cardioviruses have been thought to mainly infect rodents, a novel human cardiovirus, designated Saffold virus (SAFV), was identified in 2007. SAFV is grouped with Theiler-like rat virus and Theiler's murine encephalomyelitis virus (TMEV) in the species Theilovirus of the genus Cardiovirus of the family Picornaviridae. Eight genotypes of SAFV have now been identified. SAFV has been isolated from nasal and stool specimens from infants presenting with respiratory and gastrointestinal symptoms as well as from children with nonpolio acute flaccid paralysis; however, the relationship of SAFV to this symptomatology remains unclear. Of note, the virus has also been isolated from the cerebrospinal fluid specimens of patients with aseptic meningitis. This finding is of interest since TMEV is known to cause a multiple sclerosis-like syndrome in mice. The involvement of SAFV in various diseases (e.g., respiratory illness, gastrointestinal illness, neurological diseases, and type I diabetes) is presently under investigation. In order to clarify the pathogenicity of SAFV, additional epidemiological studies are required. Furthermore, identification of the SAFV cellular receptor will help establish an animal model for SAFV infection and help clarify the pathogenesis of SAFV-related diseases. In addition, investigation of the tissue-specific expression of the receptor may facilitate development of a novel picornavirus vector, which could be a useful tool in gene therapy for humans. The study of viral factors involved in viral pathogenicity using a reverse genetics technique will also be important.

“…Theiler's murine encephalomyelitis virus (TMEV), or Theiler's virus, is a neurotropic picornavirus responsible for either acute or persistent and demyelinating infections of the mouse central nervous system (CNS) (3). The L* protein encoded by this virus is the sole protein encoded by an alternative ORF within the picornavirus family (19). L* was found to play an important role in the establishment of persistent CNS infections by TMEV (4,7,25).…”

mentioning

confidence: 99%

Theiler's Virus L* Protein Is Targeted to the Mitochondrial Outer Membrane

Sorgeloos

Vertommen

Rider

et al. 2011

The L* protein encoded by Theiler's murine encephalomyelitis virus (TMEV) is a unique example of a picornaviral protein encoded by an alternative open reading frame. This protein is an important determinant of TMEV persistence in the mouse central nervous system. We showed that in infected cells, L* is partitioned between the cytosol and the mitochondria. In mitochondria, L* is anchored in the outer membrane and exposed to the cytosol. The targeting of L* to mitochondria is independent of other viral components and likely depends on a conformational signal. L* targeting to mitochondria might involve chaperones of the Hsp70 family, as these proteins are shown to interact.