Sensitivity of Primary Human Glioblastoma Cell Lines to Mumps Virus Vaccine Strain

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Abstract

The sensitivity of human glioblastoma cells to virus-mediated oncolysis was investigated on five patient-derived cell lines. Primary glioblastoma cells (Gbl13n, Gbl16n, Gbl17n, Gbl25n, and Gbl27n) were infected with 10-fold serial dilutions of the Leningrad-3 strain of mumps virus, virus reproduction and cytotoxicity were monitored for 96–120 hours. Immortalized human non-tumor NKE cells were used as controls to determine virus specificity. Four out of the five glioblastoma cell lines examined were susceptible to mumps virus infection, whereas no virus reproduction was observed in the non-tumor cell line. Moreover, the level of proapoptotic caspase-3 activity was increased in all infected cells 48 hours after infection. The kinetics of viral RNA accumulation in the studied glioblastoma cell lines was comparable with the rate of cell death. The data suggest that glioblastoma cell lines are permissive for mumps virus. Glioblastoma cell lines differed in type I IFN production in response to mumps virus infection. In addition, it was shown that MV infection was able to induce immunogenic death of glioblastoma cells.

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About the authors

E. Yu. Nikolaeva

Mechnikov Research Institute for Vaccines and Sera

Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 105064

Y. R. Zhelayeva

Mechnikov Research Institute for Vaccines and Sera

Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 105064

O. Yu. Susova

Mechnikov Research Institute for Vaccines and Sera

Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 105064

A. A. Mitrofanov

Blokhin Russian Cancer Research Center

Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 115478

V. O. Varachev

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 119991

T. V. Nasedkina

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences

Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 119991

V. V. Zverev

Mechnikov Research Institute for Vaccines and Sera

Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 105064

O. A. Svitich

Mechnikov Research Institute for Vaccines and Sera

Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 105064

Y. I. Ammour

Mechnikov Research Institute for Vaccines and Sera

Author for correspondence.
Email: yulia.ammour@yahoo.fr
Russian Federation, Moscow, 105064

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Supplementary files

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3. Fig. 1. Viability of five primary glioblastoma cell cultures and an immortalized NKE cell culture incubated with mumps virus (MV) strain Leningrad-3 (L-3) 3–120 h after infection. The abscissa axis shows the titer of the inoculated virus (PFU/ml), and the ordinate axis shows the cell viability (%), corresponding to the optical density values ​​of the infected cell culture expressed as a percentage of the values ​​in the uninfected culture immediately before infection (0 h), taken as 100%. The value “0” on the abscissa axis corresponds to UV-inactivated MV. Error bars indicate the standard deviation.

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4. Fig. 2. Caspase-3 activity in uninfected (mock) and MV-infected glioblastoma cells. Glioblastoma cells were infected with MV at an MOI of 1.0, and caspase-3 activity was measured after 48 h. One unit of caspase-3 activity is the amount of enzyme required to cleave 1.0 nM Ac-DEVD-pNA substrate for 1 h at 37°C. Error bars represent standard deviation.

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5. Fig. 3. Titers of mumps virus (MV) strain Leningrad-3 (L-3) calculated from the accumulation of viral RNA in glioblastoma cells Gbl13n, Gbl16n, Gbl25n, and Gbl27n. MV were collected from glioblastoma cells infected with an MOI of 0.1 (–◙-) or 1.0 (–●-) or infected with UV-inactivated MV as a control. In each reaction, threshold cycles were determined in parallel for dilutions of the standard MV sample with a known virus titer, and a calibration curve was constructed based on the results. The threshold cycle values ​​of the studied samples were plotted on it, and the values ​​expressed as lgTCID50/ml were calculated and conventionally taken as titers [16].

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6. Fig. 4. IFN-β production by MV-infected glioblastoma cells. Glioblastoma cells were infected with MV at an MOI of 1.0, and IFN-β concentrations were measured by ELISA after 24 and 48 h. K – uninfected cell cultures. Error bars indicate standard deviation. *p = 0.0244, ns: p = 0.0961.

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7. Fig. 5. Viability of Gbl13n glioblastoma cells 9–12 h after inoculation with mumps virus (MV) strain Leningrad-3 (L-3); incubation with peripheral blood mononuclear cells (PBMC); PBMC pre-stimulated with MV (PBMC/L-3), and unstimulated PBMC with simultaneous inoculation with MV (PBMC+L-3). The ordinate axis shows cell viability (%), corresponding to optical density values ​​expressed as a percentage of the values ​​for the uninfected culture, taken as 100%. Error bars indicate standard deviation. *p = 0.0192, ns: p = 0.1857.

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8. Fig. 6. NK cell activation. Flow cytometry results of PBMC cells before and after induction with mumps virus (MV). CD69 expression (%) on the surface of CD3-CD56+ cells. *p = 0.014; 0.027 and 0.122, respectively.

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