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

Abstract

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 ...

Suppression of Injuries Caused by a Lytic RNA Virus (Mengovirus) and Their Uncoupling from Viral Reproduction by Mutual Cell/Virus Disarmament

“…In this regard, it is appropriate to note that L protein of another cardiovirus, Theiler's murine encephalomyelitis virus (TMEV), may exhibit either antiapoptotic or proapoptotic activity in the strain-specific, cell-specific, and context-specific manner (23,46,55). The ability of poliovirus to elicit apoptotic response upon productive infection is markedly cell specific as well (6,28,38,42,51,60).…”

The L-Coding Region of the DA Strain of Theiler's Murine Encephalomyelitis Virus Causes Dysfunction and Death of Myelin-Synthesizing Cells

“…In order to delineate the pathogenic region within the DA5ЈUTRLL*P1 subgenomic segment, we prepared DAL/Cre mice, which express only the Recent studies have demonstrated that cardiovirus L protein has a number of activities that are likely to contribute to disease: inhibition of type I IFN gene transcription (11,35,41), inhibition of cellular mRNA export from the nucleus leading to interference with translation (6,23), and regulation of apoptosis (9,27,36). Recent in vitro studies have shown that transfection of an L expression construct of BeAn into BHK-21 cells leads to cell death and apoptosis (9) and that DA L is apoptotic in both BHK-21 and HeLa cells (36). Apoptosis has been identified in varied neural cells in the CNS after TMEV infection of mice, both early after infection and during TMEV-IDD (3, 4, 33, 39); however, the TMEV gene responsible for the apoptosis in infected neural cells has not been identified.…”

“…L protein of cardioviruses has been shown to inhibit type I interferon (IFN) gene transcription (11,35,41), inhibit nucleocytoplasmic transport and host cell translation (6,23), and regulate cell apoptosis (9,27,36).…”

Saffold Virus, a Novel Human Cardiovirus with Unknown Pathogenicity

“…TMEV L is a multifunctional protein that is important in neurovirulence, viral RNA encapsidation, anti-IFN activity, and viral persistence (29). In contrast to EMCV L protein, L protein of TMEV has a proapoptotic activity (16,42) or an antiapoptotic activity, depending on the TMEV strain and the particular cell types (57). TMEV L is thought to be an important factor in inducing the pathology found after infection of the mouse.…”