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

Arslan, Sevim Yildiz; Son, Kyung-No; Lipton, Howard L.

doi:10.1128/jvi.06516-11

Cited by 11 publications

(9 citation statements)

References 38 publications

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“…One-step growth kinetics of BeAn virus in M1-D macrophages (moi = 10) peak at 10 to 12 h pi, when virion assembly is complete, yielding ~150 pfu/cell before the onset of apoptosis, followed by almost total loss of infectious virus (<5 pfu/cell) by 20 to 24 h pi (Son et al, 2008; Yildiz Arslan et al, 2012). Treatment of infected cell monolayers with qVD-OPh restored >70% of viral titers at 16 and 20 h pi (p>0.05; p<0.001 at 24 and p<0.01 at 30 h pi), when RIP1 had been activated and necroptosis was underway (Fig.…”

Section: Necroptosis and Bean Viral Yieldsmentioning

confidence: 99%

Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis

Son

Lipton

2015

Virus Research

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In mice Theiler’s murine encephalomyelitis virus (TMEV) persists in macrophages that eventually undergo apoptosis. TMEV infection of macrophages in culture induces apoptosis through the intrinsic pathway, restricting virus yields. We show that inhibition of TMEV-induced apoptosis leads to phosphorylation of receptor interacting protein 1 (RIP1), localization of RIP1 and RIP3 to mitochondria, ROS production independent of MAPK activation and programmed necrosis (necroptosis). Blocking both apoptotis and necroptosis restored virus yields.

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Section: Necroptosis and Bean Viral Yieldsmentioning

confidence: 99%

Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis

Son

Lipton

2015

Virus Research

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“…Differences were considered significant at a P value of Ͻ0.05. (10,19), and BHK-21 cells, which undergo necroptosis with high virus yields (11), is provided in Fig. 1.…”

Section: Methodsmentioning

confidence: 99%

“…TMEV has been shown to selectively induce apoptosis in murine macrophages in vitro (9,10), unlike the case for infection of other somatic cells such as BHK-21 cells, which undergo programmed necrosis or necroptosis (11). TMEV-induced apoptosis occurs via the intrinsic pathway, initiated by activation of MKKK3/6 and p38 mitogen-activated protein kinase (MAPK) and leading to phosphorylation and activation of p53 and, in turn, upregulation of expression of the proapoptotic BH3-only proteins Noxa and Puma, which bind BH multidomain antiapoptotic pro-teins Mcl-1 and A1 (12).…”

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confidence: 99%

During Infection, Theiler's Virions Are Cleaved by Caspases and Disassembled into Pentamers

Arslan

Son

Lipton

2016

J Virol

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Infected macrophages in spinal cords of mice persistently infected with Theiler's murine encephalomyelitis virus (TMEV) undergo apoptosis, resulting in restricted virus yields, as do infected macrophages in culture. Apoptosis of murine macrophages in culture occurs via the intrinsic pathway later in infection (>10 h postinfection [p.i.]) after maximal virus titers (150 to 200 PFU/ cell) have been reached, with loss of most infectious virus (<5 PFU/cell) by 20 to 24 h p.i. Here, we show that BeAn virus RNA replication, translation, polyprotein processing into final protein products, and assembly of protomers and pentamers in infected M1-D macrophages did not differ from those processes in TMEV-infected BHK-21 cells, which undergo necroptosis. However, the initial difference from BHK-21 cell infection was seen at 10 to 12 h p.i., where virions from the 160S peak in sucrose gradients had incompletely processed VP0 (compared to that in infected BHK-21 cells). Thereafter, there was a gradual loss of the 160S virion peak in sucrose gradients, with replacement by a 216S peak that was observed to contain pentamers among lipid debris in negatively stained grids by electron microscopy. After infection or incubation of purified virions with activated caspase-3 in vitro, 13-and 17-kDa capsid peptide fragments were observed and were predicted by algorithms to contain cleavage sites within proteins by cysteine-dependent aspartate-directed proteases. These findings suggest that caspase cleavage of sites in exposed capsid loops of assembled virions occurs contemporaneously with the onset and progression of apoptosis later in the infection. IMPORTANCETheiler's murine encephalomyelitis virus (TMEV) infection in mice results in establishment of virus persistence in the central nervous system and chronic inflammatory demyelinating disease, providing an experimental animal model for multiple sclerosis. Virus persistence takes place primarily in macrophages recruited into the spinal cord that undergo apoptosis and in turn may facilitate viral spread via infected apoptotic blebs. Infection of murine macrophages in culture results in restricted virus yields late in infection. Here it is shown that the early steps of the virus life cycle in infected macrophages in vitro do not differ from these processes in TMEV-infected BHK-21 cells, which undergo necroptosis. However, the findings late in infection suggest that caspases cleave sites in exposed capsid loops and possibly internal sites of assembled virions occurring contemporaneously with onset and progression of apoptosis. Mechanistically, this would explain the dramatic loss in virus yields during TMEV-induced apoptosis and attenuate the virus, enabling persistence. L ow-neurovirulence Theiler's murine encephalomyelitis viruses (TMEV) establish a persistent central nervous system (CNS) infection in susceptible strains of mice, resulting in cytolytic death of oligodendrocytes and subsequent immune-mediated damage to myelin with myelin breakdown (1-4). Autoreactive CD4 ϩ Th1 T l...

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“…Furthermore, the response to picornavirus of a given population is very rarely, if ever, homogeneous. Usually, it is possible only to identify the predominant reaction, and both apoptotic and necrotic cells are present in noticeable proportions in some cases [50,51].…”

Section: Inhibitor Of Viral Replicaɵonmentioning

confidence: 99%

Cytopathic effects: virus-modulated manifestations of innate immunity?

Agol

2012

Trends in Microbiology

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The capacity to injure infected cells is a widespread property of viruses. Usually, this cytopathic effect (CPE) is ascribed to viral hijacking of cellular resources to fulfill viral needs. However, evidence is accumulating that CPE is not necessarily directly coupled to viral reproduction but may largely be due to host defensive and viral antidefensive activities. A major part in this virus-cell interaction appears to be played by a putative host-encoded program with multiple competing branches, leading to necrotic, apoptotic, and, possibly, other types of cell suicide. Manifestations of this program are controlled and modulated by host, viral, and environmental factors.

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

Cited by 11 publications

References 38 publications

Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis

Inhibition of Theiler's virus-induced apoptosis in infected murine macrophages results in necroptosis

During Infection, Theiler's Virions Are Cleaved by Caspases and Disassembled into Pentamers

Cytopathic effects: virus-modulated manifestations of innate immunity?

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