Measles virus induces apoptosis in uninfected bystander T cells and leads to granzyme B and caspase activation in peripheral blood mononuclear cell cultures

Vuorinen, Tytti; Peri, Piritta; Vainionpää, Raija

doi:10.1046/j.1365-2362.2003.01164.x

Cited by 32 publications

(30 citation statements)

References 34 publications

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“…Fas loss of function or expression has been reported to accompany malignant phenotypes (55). Measles virus infection has previously been shown to result in Fas up-regulation in peripheral blood mononuclear cells (25) and dendritic cells (24), both in cell culture and in measles patients (26). Fas upregulation is also a significant determinant of lymphopenia observed in the context of natural measles virus infection (26).…”

Section: Discussionmentioning

confidence: 99%

Combination of Measles Virus Virotherapy and Radiation Therapy Has Synergistic Activity in the Treatment of Glioblastoma Multiforme

Liu¹,

Sarkaria

Petell³

et al. 2007

Clinical Cancer Research

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Purpose: Glioblastoma multiforme is the most frequent primary brain tumor in adults and represents one of the most lethal malignancies with a median survival of 12-16 months.We have previously shown that an oncolytic measles virus derivative expressing soluble human carcinoembryonic antigen (MV-CEA) has significant antitumor activity against glioblastoma multiforme cell lines and xenografts. Radiation therapy (RT) represents one of the mainstays of glioma treatment. Here we tested the hypothesis that the combination of RTwith MV-CEA would have synergistic activity against gliomas. Experimental Design: 3-(4,5-Dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and clonogenic assays were used to test cytoxicity of the combination treatment in vivo. To examine the mechanism of synergy, one-step viral growth curves, terminal deoxyribonucleotidyl transferase^mediated dUTP nick end labeling (TUNEL) assays, and Western blot analyses were performed. In vivo assessment of synergistic antitumor activity was conducted in a U87 glioma model. Results: MTS and clonogenic assays showed a strong synergistic interaction between MV-CEA and RT in glioblastoma multiforme cells including both primary and established glioma lines. Furthermore, significant antitumor efficacy was observed in vivo in a subcuteneous U87 xenograph model. There was significant prolongation of survival (P = 0.001) in the combination treatment group as compared with single modality^or control-treated animals. One-step viral growth curves showed increased viral burst size by up to 2 log in MV/RTcombination^treated cells, as compared with single agent MV-CEA^treated glioma cells. Changes in CEA levels and expression of viral N and H protein were also consistent with increased viral production. Furthermore,TUNEL assays and Western blot analysis showed increase in apoptosis in MV/RT combination^treated cells. The pan-caspase inhibitor Z-VAD-FMK and the caspase-8 inhibitor Z-IETD-FMK, but not the caspase-9 inhibitor Z-IEHD-FMK, protected glioma cells from MV-CEA/ RT^induced cleavage of poly(ADP-ribose) polymerase (PARP), indicating that the apoptotic death in combination-treated cells is mostly mediated via the extrinsic caspase pathway. The Fas/Fas ligand interaction blocking antibody NOK-1blocked MV/RT^induced PARP cleavage whereas the Fas agonistic antibody CH11increased PARP cleavage in MV/RTcombination^treated cells. Reverse transcription-PCR, fluorescence-activated cell sorting analysis and immunohistochemistry showed up-regulation of Fas in combination-treated tumor in vitro and in vivo cells. Conclusions: There is synergy between MV-CEA and RT in vitro and in vivo. The synergistic effect of the combination seems to be due to increase in viral burst size and increase in apoptotic cell death. This latter effect is mostly mediated via the extrinsic caspase-8 pathway, activated via increased signaling through the Fas death receptor pathway.These results could have translational implications in glioma therapy.

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Section: Discussionmentioning

confidence: 99%

Combination of Measles Virus Virotherapy and Radiation Therapy Has Synergistic Activity in the Treatment of Glioblastoma Multiforme

Liu¹,

Sarkaria

Petell³

et al. 2007

Clinical Cancer Research

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“…Interestingly, there has been no report that Vero cells express FasL, so it seems unlikely that apoptosis in CDV-infected Vero cells was triggered by the FasL-bound Fas receptor. In the case of measles virus (MV), which belongs to the genus Morbillivirus, MV-infected peripheral blood mononuclear cells (Vuorinen et al, 2003) and dendritic cells (Servet-Delprat et al, 2000a) have been shown to induce apoptosis in uninfected T cells via the Fas/FasL pathway (Servet-Delprat et al, 2000b). With respect to the Sendai virus (Sv), which, like CDV, belongs to the subfamily Paramyxovirinae, it has been reported that induction of host cell apoptosis by Sv in vitro requires the activation of caspase-8 but does not require FasL (Bitzer et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Vero cells infected with the Lederle strain of canine distemper virus have increased Fas receptor signaling expression at 15 h post-infection

Puerto¹,

Martins²,

Braz³

et al. 2011

Genet. Mol. Res.

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“…In the case of morbilliviruses, infection-induced apoptosis of immune cells has been proposed as a main factor contributing to the observed leukopenia and the resulting immune suppression (10). There is experimental evidence for apoptosis induction, either directly in infected cells or as a bystander effect in noninfected cells (18,25,41), as well as for inhibition of apoptosis in the context of viral interference with the host response on a cellular level (7,37). To gain better insight in the extent of apoptosis in immune tissues during the crucial early stages of a natural infection, we assessed levels of early and late apoptosis at different time points during the first week after infection in ferrets infected with a wild-type CDV strain.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, bystander apoptosis of noninfected CD3 ϩ cells has been observed after in vitro infection of human peripheral blood mononuclear cells (PBMCs) (12,41). These observations have been supported by direct analyses of PBMCs from MeV patients, where high levels of proapoptotic noninfected cells were found (25,26).…”

mentioning

confidence: 84%

Canine Distemper Virus Selectively Inhibits Apoptosis Progression in Infected Immune Cells

Pillet

Messling

2009

J Virol

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Morbillivirus infections are characterized by severe leukopenia and immune suppression that develop even before the onset of clinical signs. To characterize in more detail the fate of the immune cells during the critical first week, we evaluated the overall viability, level of apoptosis, cell cycle status, and extent of infection in different immune tissues of ferrets inoculated with a lethal canine distemper virus (CDV) strain. Initial experiments with MDCK cells, a canine epithelial cell line, revealed that CDV infection resulted in only a marginal increase in apoptosis at high infection levels and that infected cells were more resistant to chemically induced apoptosis. In ferrets, levels of viability and early and late apoptosis remained stable in thymus and lymph node, where more than 80% of cells were infected, whereas a gradual albeit small increase in apoptosis was observed in peripheral blood mononuclear cells and spleen. Furthermore, the progression of spontaneous apoptosis in infected cells was inhibited, while the proportion of apoptotic noninfected "bystander" cells increased. The distribution of cells in the different stages of the cell cycle in the bone marrow was not affected, but dividing cells in the thymus decreased by 50%, and a 10-fold increase in cell division was noted in the spleen. It is unlikely that the extent of infection-induced cell death and cell cycle alterations alone can account for the dramatic leukopenia observed in this model. The investigation of additional mechanisms is therefore warranted.

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Measles virus induces apoptosis in uninfected bystander T cells and leads to granzyme B and caspase activation in peripheral blood mononuclear cell cultures

Cited by 32 publications

References 34 publications

Combination of Measles Virus Virotherapy and Radiation Therapy Has Synergistic Activity in the Treatment of Glioblastoma Multiforme

Combination of Measles Virus Virotherapy and Radiation Therapy Has Synergistic Activity in the Treatment of Glioblastoma Multiforme

Vero cells infected with the Lederle strain of canine distemper virus have increased Fas receptor signaling expression at 15 h post-infection

Canine Distemper Virus Selectively Inhibits Apoptosis Progression in Infected Immune Cells

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