Abstract
Sindbis virus (SV) is an alphavirus used as a model for studying the pathogenesis of viral encephalitis. In this study we examined the effects and the mechanisms involved in the apoptosis induced by SV in PC-12 cells, and the role of a vFLIP in this process. Infection of PC-12 cells with a neurovirulent strain of SV, SVNI, induced cell apoptosis. Overexpression of vFLIP encoded by the HHV-8 or treatment with a caspase-8 inhibitor inhibited cell apoptosis. SVNI induced an increase in the expression of tumor necrosis factor α (TNF-α), and pre-treatment of the cells with an anti-TNF-α blocking antibody or with soluble TNF-α receptor abrogated the apoptotic effect of SVNI. Moreover, TNF-αR1 knockout mice were more resistant to the cytopathic effects of the virus as compared to control animals. Our results indicate that the apoptosis induced by SVNI is mediated by activation of caspase-8, and that TNF-α plays an important role in the apoptotic response. Cell Death and Differentiation (2001) 8, 1224–1231
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Abbreviations
- SV:
-
Sindbis virus
- TNF-α:
-
tumor necrosis factor α
- FLIP:
-
FLICE inhibitory protein
References
Raff MC . 1992 Social controls on cell survival and cell death Nature 356: 397–400
Thompson CB . 1995 Apoptosis in the pathogenesis and treatment of disease Science 267: 1456–1462
Wertz IE, Hanley MR . 1996 Diverse molecular provocation of programmed cell death Trends Biochem. Sci. 21: 359–364
White E . 1996 Life, death, and the pursuit of apoptosis Genes Dev. 10: 1–15
Teodoro JG, Branton PE . 1997 Regulation of apoptosis by viral gene products J. Virol. 71: 1739–1746
Roulston A, Marcellus RC, Branton PE . 1999 Viruses and apoptosis Ann. Rev. Microbiol. 53: 577–628
Griffin DE, Hardwick JM . 1997 Regulators of apoptosis on the road to persistent alphavirus infection Annu. Rev. Microbiol. 51: 565–592
Griffin DE, Hardwick JM . 1999 Perspective: virus infections and the death of neurons Trends Microbiol. 7: 155–160
Levine B, Huang Q, Isaacs JT, Reed JC, Griffin DE, Hardwick JM . 1993 Conversion of lytic to persistent alphavirus infection by the bcl-2 cellular oncogene Nature 361: 739–742
Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, Herman B, Levine B . 1998 Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein J. Virol. 72: 8586–8596
Griffin DE . 1998 A review of alphavirus replication in neurons Neurosci. Biobehav. Rev. 22: 721–723
Nava VE, Rosen A, Veliuona MA, Clem RJ, Levine B, Hardwick JM . 1998 Sindbis virus induces apoptosis through a caspase-dependent, CrmA-sensitive pathway J. Virol. 72: 452–459
Wallach D . 1997 Cell death induction by TNF: a matter of self control Trends Biochem. Sci. 22: 107–109
Porter AG . 1999 Protein translocation in apoptosis Trends Cell. Biol. 9: 394–401
Cohen GM . 1997 Caspases: the executioners of apoptosis Biochem. J. 326: 1–16
Hu S, Vincenz C, Buller M, Dixit VM . 1997 A novel family of viral death effector domain-containing molecules that inhibit both CD-95- and tumor necrosis factor receptor-1-induced apoptosis J. Biol. Chem. 272: 9621–9624
Thome M, Schneider P, Hofmann K, Fickenscher H, Meinl E, Neipel F, Mattmann C, Burns K, Bodmer JL, Schroter M, Scaffidi C, Krammer PH, Peter ME, Tschopp J . 1997 Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors Nature 386: 517–521
Goltsev YV, Kovalenko AV, Arnold E, Varfolomeev EE, Brodianskii VM, Wallach D . 1997 CASH, a novel caspase homologue with death effector domains J. Biol. Chem. 272: 19641–19644
Irmler M, Thome M, Hahne M, Schneider P, Hofmann K, Steiner V, Bodmer JL, Schroter M, Burns K, Mattmann C, Rimoldi D, French LE, Tschopp J . 1997 Inhibition of death receptor signals by cellular FLIP Nature 388: 190–195
Srinivasula SM, Ahmad M, Ottilie S, Bullrich F, Banks S, Wang Y, Fernandes-Alnemri T, Croce CM, Litwack G, Tomaselli KJ, Armstrong RC, Alnemri ES . 1997 FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates Fas/TNFR1-induced apoptosis J. Biol. Chem. 272: 18542–18545
Lustig S, Halevy M, Ben Nathan D, Akov Y . 1992 A novel variant of Sindbis virus is both neurovirulent and neuroinvasive in adult mice Arch. Virol. 122: 237–248
Appel E, Katzoff A, Ben Moshe T, Kazimirsky G, Kobiler D, Lustig S, Brodie C . 2000 Differential regulation of bcl-2 and bax expression in cells infected with virulent and nonvirulent strains of sindbis virus [in process citation] Virology 276: 238–242
Bertin J, Armstrong RC, Ottilie S, Martin DA, Wang Y, Banks S, Wang GH, Senkevich TG, Alnemri ES, Moss B, Lenardo MJ, Tomaselli KJ, Cohen JI . 1997 Death effector domain-containing herpesvirus and poxvirus proteins inhibit both Fas- and TNFR1-induced apoptosis Proc. Natl. Acad. Sci. USA 94: 1172–1176
Martin DA, Siegel RM, Zheng L, Lenardo MJ . 1998 Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha 1) death signal J. Biol. Chem. 273: 4345–4349
Brodie C, Weizman N, Katzoff A, Lustig S, Kobiler D . 1997 Astrocyte activation by Sindbis virus: expression of GFAP, cytokines, and adhesion molecules Glia 19: 275–285
Gomez dM, Ortuno E, Fernandez-Zapatero P, Alonso F, Alonso C, Ezquerra A, Dominguez J . 1999 African swine fever virus infection induces tumor necrosis factor alpha production: implications in pathogenesis J. Virol. 73: 2173–2180
Antoni BA, Sabbatini P, Rabson AB, White E . 1995 Inhibition of apoptosis in human immunodeficiency virus-infected cells enhances virus production and facilitates persistent infection J. Virol. 69: 2384–2392
Chinnaiyan AM, Woffendin C, Dixit VM, Nabel GJ . 1997 The inhibition of pro-apoptotic ICE-like proteases enhances HIV replication Nat. Med. 3: 333–337
Scallan MF, Allsopp TE, Fazakerley JK . 1997 bcl-2 acts early to restrict Semliki Forest virus replication and delays virus-induced programmed cell death J. Virol. 71: 1583–1590
Olsen CW, Kehren JC, Dybdahl-Sissoko NR, Hinshaw VS . 1996 bcl-2 alters influenza virus yield, spread, and hemagglutinin glycosylation J. Virol. 70: 663–666
Chaudhary PM, Jasmin A, Eby MT, Hood L . 1999 Modulation of the NF-kappa B pathway by virally encoded death effector domains-containing proteins Oncogene 18: 5738–5746
Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP . 1999 Tumor necrosis factor receptor and Fas signaling mechanisms Annu. Rev. Immunol. 17: 331–367
Vilcek J, Sen GC . 1996 Interferons and other cytokines. In Fields Virology, Fields BN, Knipe DM and Howley PM, eds Philadelphia: Lippincott-Raven pp. 375–399
Osborn L, Kunkel S, Nabel GJ . 1989 Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B Proc. Natl. Acad. Sci. USA 86: 2336–2340
Zhu N, Khoshnan A, Schneider R, Matsumoto M, Dennert G, Ware C, Lai MM . 1998 Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis J. Virol. 72: 3691–3697
Lorence RM, Rood PA, Kelley KW . 1988 Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity J. Natl. Cancer Inst. 80: 1305–1312
Inoue Y, Yasukawa M, Fujita S . 1997 Induction of T-cell apoptosis by human herpesvirus 6 J. Virol. 71: 3751–3759
Strauss EG, Lenches EM, Strauss JH . 1976 Mutants of sindbis virus. I. Isolation and partial characterization of 89 new temperature-sensitive mutants Virology 74: 154–168
Kobiler D, Rice CM, Brodie C, Shahar A, Dubuisson J, Halevy M, Lustig S . 1999 A single nucleotide change in the 5′ noncoding region of Sindbis virus confers neurovirulence in rats J. Virol. 73: 10440–10446
Pfeffer K, Matsuyama T, Kundig TM, Wakeham A, Kishihara K, Shahinian A, Wiegmann K, Ohashi PS, Kronke M, Mak TW . 1993 Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection Cell 73: 457–467
Brodie C, Bogi K, Acs P, Lazarovici P, Petrovics G, Anderson WB, Blumberg PM . 1999 Protein kinase C-epsilon plays a role in neurite outgrowth in response to epidermal growth factor and nerve growth factor in PC12 cells Cell Growth Differ. 10: 183–191
Chomczynski P, Sacchi N . 1987 Single step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction Anal. Biochem. 162: 156–159
Acknowledgements
This work was supported by Israel Science Foundation grant 72696-16.6. We wish to thank. Paula Schneider for the excellent technical assistance and Avrille Goldreich for the skillful preparation of the manuscript.
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Sarid, R., Ben-Moshe, T., Kazimirsky, G. et al. vFLIP protects PC-12 cells from apoptosis induced by Sindbis virus: implications for the role of TNF-α. Cell Death Differ 8, 1224–1231 (2001). https://doi.org/10.1038/sj.cdd.4400926
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DOI: https://doi.org/10.1038/sj.cdd.4400926
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