Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death

Kuo, Rei-Lin; Kung, Szu Hao; Hsu, Yueh-Ying; Liu, Wu-Tse

doi:10.1099/0022-1317-83-6-1367

Cited by 128 publications

(114 citation statements)

References 68 publications

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“…Among picornaviruses, coxsackievirus B3 1B (VP2) (12,13), avian encephalomyocarditis virus 1C (VP3) (24) and 2C (25), enterovirus 71 2A (20), and poliovirus 2A (10) and 3C protease (3C pro ) (3) induce apoptosis, mostly through the intrinsic pathway. Coxsackievirus B3 VP2 has been shown to interact with the proapoptotic Siva protein in a yeast two-hybrid screen (12), but exactly how the VP2-Siva interaction or any of the other picornavirus proteins initiates the apoptotic cascade remains unknown.…”

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confidence: 99%

Theiler's Murine Encephalomyelitis Virus Leader Protein Is the Only Nonstructural Protein Tested That Induces Apoptosis When Transfected into Mammalian Cells

Fan¹,

Son

Arslan

et al. 2009

J Virol

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Theiler's murine encephalomyelitis virus (TMEV) induces two distinct cell death programs, necrosis and apoptosis. The apoptotic pathway is of particular interest because TMEV persists in the central nervous system of mice, largely in infiltrating macrophages, which undergo apoptosis. Infection of murine macrophages in culture induces apoptosis that is Bax dependent through the intrinsic or mitochondrial pathway, restricting infectious-virus yields and raising the possibility that apoptosis represents a mechanism to attenuate TMEV yet promote macrophage-to-macrophage spread during persistent infection. To help define the cellular stressors and upstream signaling events leading to apoptosis during TMEV infection, we screened baby hamster kidney (BHK-21) cells transfected to express individual nonstructural genes (except 3B) of the low-neurovirulence BeAn virus strain for cell death. Only expression of the leader protein led to apoptosis, as assessed by fluorescence-activated cell sorting analysis of propidium iodide-and annexin V-stained transfected cells, immunoblot analysis of poly(ADP-ribose) polymerase and caspase cleavages, electron microscopy, and inhibition of apoptosis by the pancaspase inhibitor qVD-OPh. After transfection, Bak and not Bax expression increased, suggesting that the apical pathway leading to activation of these Bcl-2 multi-BH-domain proapoptotic proteins differs in BeAn virus infection versus L transfection. Mutation to remove the CHCC Zn finger motif from L, a motif required by L to mediate inhibition of nucleocytoplasmic trafficking, significantly reduced L-protein-induced apoptosis in both BHK-21 and M1-D macrophages.Theiler's murine encephalomyelitis viruses (TMEV), members of the genus Cardiovirus in the family Picornaviridae, are highly cytolytic RNA viruses. Mice experimentally infected with a low-neurovirulence TMEV, such as BeAn virus, develop persistent infection in the central nervous system (CNS) and an inflammatory demyelinating disease, providing an experimental analogue for multiple sclerosis. BeAn virus persists primarily in macrophages in the CNS of infected mice. Schlitt et al. (34) found that 74% of TUNEL-positive cells in infected spinal cords (primarily in CNS lesions) were T and B lymphocytes and 8% were macrophages, although virus genomes were detected in Ͻ1% of apoptotic cells, consistent with infection of only a low percentage of macrophages and the fact that TMEV does not infect T or B lymphocytes in culture. Thus, some means other than direct infection was responsible for apoptosis of most CNS macrophages, including TMEV triggering apoptosis through tumor necrosis factor alpha or tumor necrosis factor alpha-related apoptosis-inducing ligand by binding death receptors on activated macrophages in vitro, as reported elsewhere (17).Infection of mouse macrophages induces apoptosis (16, 26) mediated by Bax through the intrinsic or mitochondrial pathway and severely restricts the yield of progeny virus (37). Thus, apoptosis may be a mechanism to attenuate the virus yet...

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confidence: 99%

Theiler's Murine Encephalomyelitis Virus Leader Protein Is the Only Nonstructural Protein Tested That Induces Apoptosis When Transfected into Mammalian Cells

Fan¹,

Son

Arslan

et al. 2009

J Virol

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“…However, the expressions of EV70 major capsid proteins did not correlate with the apoptosis of SRA01/04 or HCC cells, leading us to believe that EV70 major capsid proteins are not directly involved in the apoptosis induction in both cell lines although this needs further support from future functional experiments. In addition, poliovirus 2A protease [37,38] and 3C protease [39,40] and EV71 2A protease [41] were reported to induce apoptosis of host cells. In our study, high concentrations of MPCMK and elastatinal (inhibitors of poliovirus or rhinovirus 2A protease) inhibited EV70 induced cell death of SRA01/04 cells by apoptosis, suggesting that EV70 2A protease protein produced during EV70 replication directly induces apoptosis of host cells.…”

Section: Discussionmentioning

confidence: 99%

“…PFU/cell for 24 hrs could induce apparent apoptotic DNA ladders (Fig. 1A), (b) in the one-step growth experiment [22] , EV70 infection at an m.o.i. > 10 PFU/cell could induce apoptotic DNA ladders (Fig.…”

Section: Methodsmentioning

confidence: 99%

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Induction of Caspase-dependant Apoptosis by Enterovirus 70 in Human Lens Epithelial SRA01/04 Cells

Chen¹,

Duggan²,

Texada³

et al. 2005

American J. of Infectious Diseases

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Enterovirus 70 (EV70), an etiological agent of acute hemorrhagic conjunctivitis (AHC), induces apoptosis in human Chang's conjunctival (HCC) cells. EV70 is also able to infect and replicate in some other human cells such as human lens epithelial SRA01/04 cells and U937 cells. EV70 infection was found to induce apoptosis in SRA01/04 cells. During EV70-induced apoptosis of SRA01/04 cells, the expression levels of procaspase-3, 6 and 7 (all 32kD) were not increased, but procaspase-3 and 7 were activated (cleaved) while the constitutively activated caspase-6 decreased. Z-VD-FMK inhibited EV70-induced apoptosis and extracellular EV70 release, but not intracellular viral production. UV-or heat-inactivated EV70 did not induce apoptosis. Guanidine⋅HCl inhibited EV70 induced apoptosis in a multiple-step viral growth experiment but not in a one-step viral growth experiment. Cycloheximide and high concentration of methoxysuccinyl-Ala-Ala-Pro-Val-chloromethylketone (MPCMK) (0.5 mM) or elastatinal (Ela) (125 mM) also inhibited EV70-induced apoptosis. The results suggest that infectious EV70 is capable of inducing caspase-dependent (especially caspases-3 and 7-dependent) apoptosis in human lens SRA01/04 cells that requires the syntheses of viral proteins, but not viral genome RNA. The results suggest that (a) EV70 protease(s) (2A protease and probably 3C protease) produced during viral replication initiates EV70 induced apoptosis of SRA01/04 cells and (b) EV70 may use similar or same mechanism(s) to induce apoptosis in different human cells such as SRA01/04 and HCC cells.

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“…In picornavirus infections where rapid viral replication kinetics usually predominate, necrosis generally has been associated with productive infections and apoptosis with restricted infections (6,15,18,31,34). TMEV infection has been shown to induce necrosis in rodent cells, such as BHK-21 and L929 cells, in association with high viral yields (15,32), whereas murine Ms undergo apoptosis exclusively, with interruption of virus production and decreased yields of infectious virus progeny.…”

Section: Discussionmentioning

confidence: 99%

The Antiapoptotic Protein Mcl-1 Controls the Type of Cell Death in Theiler's Virus-Infected BHK-21 Cells

Arslan

Son

Lipton

2012

J Virol

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Theiler's murine encephalomyelitis virus (TMEV) results in a persistent central nervous system infection (CNS) and immunemediated demyelination in mice. TMEV largely persists in macrophages (Ms) in the CNS, and infected Ms in vitro undergo apoptosis, whereas the infection of other rodent cells produces necrosis. We have found that necrosis is the dominant form of cell death in BeAn virus-infected BHK-21 cells but that ϳ20% of cells undergo apoptosis. Mcl-1 was highly expressed in BHK-21 cells, and protein levels decreased upon infection, consistent with onset of apoptosis. In infected BHK-21 cells in which Mcl-1 expression was knocked down using silencing RNAs there was a 3-fold increase in apoptotic cell death compared to parental cells. The apoptotic program switched on by BeAn virus is similar to that in mouse Ms, with hallmarks of activation of the intrinsic apoptotic pathway in a tumor suppressor protein p53-dependent manner. Infection of stable Mcl-1-knockdown cells led to restricted virus titers and increased physical to infectious particle (PFU) ratios, with additional data suggesting that a late step in the viral life cycle after viral RNA replication, protein synthesis, and polyprotein processing is affected by apoptosis. Together, these results indicate that Mcl-1 acts as a critical prosurvival factor that protects against apoptosis and allows high yields of infectious virus in BHK-21 cells.

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Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death

Cited by 128 publications

References 68 publications

Theiler's Murine Encephalomyelitis Virus Leader Protein Is the Only Nonstructural Protein Tested That Induces Apoptosis When Transfected into Mammalian Cells

Theiler's Murine Encephalomyelitis Virus Leader Protein Is the Only Nonstructural Protein Tested That Induces Apoptosis When Transfected into Mammalian Cells

Induction of Caspase-dependant Apoptosis by Enterovirus 70 in Human Lens Epithelial SRA01/04 Cells

The Antiapoptotic Protein Mcl-1 Controls the Type of Cell Death in Theiler's Virus-Infected BHK-21 Cells

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