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Diverse apoptotic pathways in enterovirus 71-infected cells

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Abstract

Mechanisms related to the neuropathogenesis of enterovirus 71 infection remain unclear. This investigation conducts a comprehensive study of the apoptotic pathways in neural and non-neural cells following enterovirus 71 infection. Infections with enterovirus 71 not only induce classical cytopathic effects in SF268 (human glioblastoma), SK-N-MC (human neuroblastoma), RD, and Vero cells, but also induce classic signs of apoptosis in all cells, including DNA fragmentation and phosphatidylserine translocation. Apoptosis has also been caused by the efflux of cytochrome c from mitochondria, and subsequently by cleavage of caspase 9 in all cells. Activation of caspase 8 followed by cleavage of the proapoptotic protein Bid only occurs in non-neural cells. Results of this study demonstrate that a mitochondrial pathway of apoptosis mediated by activation and cleavage of caspase 9 is a main pathway in enterovirus 71-induced apoptosis, especially for enterovirus 71-infected neural cells.

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References

  • Adams JM (2003). Ways of dying: multiple pathways to apoptosis. Genes Dev 17: 2481–2495.

    Article  CAS  PubMed  Google Scholar 

  • Adrain C, Martin SJ (2001). The mitochondrial apoptosome: a killer unleashed by the cytochrome seas. Trends Biochem Sci 26: 390–397.

    Article  CAS  PubMed  Google Scholar 

  • Alexander JP Jr, Baden L, Pallansch MA, Anderson LJ (1994). Enterovirus 71 infections and neurologic disease—United States, 1977–1991. J Infect Dis 169: 905–908.

    PubMed  Google Scholar 

  • Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J (1996). Human ICE/CED-3 protease nomenclature. Cell 87: 171.

    Article  CAS  PubMed  Google Scholar 

  • Barber GN (2001). Host defense, viruses and apoptosis. Cell Death Differ 8: 113–126.

    Article  CAS  PubMed  Google Scholar 

  • Barco A, Feduchi E, Carrasco L (2000). Poliovirus protease 3C(pro) kills cells by apoptosis. Virology 266: 352–360.

    Article  CAS  PubMed  Google Scholar 

  • Belov GA, Romanova LI, Tolskaya EA, Kolesnikova MS, Lazebnik YA, Agol VI (2003). The major apoptotic pathway activated and suppressed by poliovirus. J Virol 77: 45–56.

    Article  CAS  PubMed  Google Scholar 

  • Blomberg J, Lycke E, Ahlfors K, Johnsson T, Wolontis S, von Zeipel G (1974). Letter: new enterovirus type associated with epidemic of aseptic meningitis and-or hand, foot, and mouth disease. Lancet 2: 112.

    Article  CAS  PubMed  Google Scholar 

  • Bossy-Wetzel E, Green DR (1999). Caspases induce cytochrome c release from mitochondria by activating cytosolic factors. J Biol Chem 274: 17484–17490.

    Article  CAS  PubMed  Google Scholar 

  • Bouillet P, Purton JF, Godfrey DI, Zhang LC, Coultas L, Puthalakath H, Pellegrini M, Cory S, Adams JM, Strasser A (2002). BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes. Nature 415: 922–926.

    Article  CAS  PubMed  Google Scholar 

  • Buendia B, Santa-Maria A, Courvalin JC (1999). Caspasedependent proteolysis of integral and peripheral proteins of nuclear membranes and nuclear pore complex proteins during apoptosis. J Cell Sci 112(Pt 11): 1743–1753.

    CAS  PubMed  Google Scholar 

  • Chang LY, Lin TY, Hsu KH, Huang YC, Lin KL, Hsueh C, Shih SR, Ning HC, Hwang MS, Wang HS, Lee CY (1999). Clinical features and risk factors of pulmonary oedema after enterovirus-71-related hand, foot, and mouth disease. Lancet 354: 1682–1686.

    Article  CAS  PubMed  Google Scholar 

  • Chen YC, Yu CK, Wang YF, Liu CC, Su IJ, Lei HY (2004). A murine oral enterovirus 71 infection model with central nervous system involvement. J Gen Virol 85: 69–77.

    Article  CAS  PubMed  Google Scholar 

  • Chonmaitree T, Menegus MA, Schervish-Swierkosz EM, Schwalenstocker E (1981). Enterovirus 71 infection: report of an outbreak with two cases of paralysis and a review of the literature. Pediatrics 67: 489–493.

    CAS  PubMed  Google Scholar 

  • Chou JJ, Li H, Salvesen GS, Yuan J, Wagner G (1999). Solution structure of BID, an intracellular amplifier of apoptotic signaling. Cell 96: 615–624.

    Article  CAS  PubMed  Google Scholar 

  • Chumakov M, Voroshilova M, Shindarov L, Lavrova I, Gracheva L, Koroleva G, Vasilenko S, Brodvarova I, Nikolova M, Gyurova S, Gacheva M, Mitov G, Ninov N, Tsylka E, Robinson I, Frolova M, Bashkirtsev V, Martiyanova L, Rodin V (1979). Enterovirus 71 isolated from cases of epidemic poliomyelitis-like disease in Bulgaria. Arch Virol 60: 329–340.

    Article  CAS  PubMed  Google Scholar 

  • Couderc T, Guivel-Benhassine F, Calaora V, Gosselin AS, Blondel B (2002). An ex vivo murine model to study poliovirus-induced apoptosis in nerve cells. J Gen Virol 83: 1925–1930.

    CAS  PubMed  Google Scholar 

  • Despres P, Flamand M, Ceccaldi PE, Deubel V (1996). Human isolates of dengue type 1 virus induce apoptosis in mouse neuroblastoma cells. J Virol 70: 4090–4096.

    CAS  PubMed  Google Scholar 

  • Duncan R, Muller J, Lee N, Esmaili A, Nakhasi HL (1999). Rubella virus-induced apoptosis varies among cell lines and is modulated by Bcl-XL and caspase inhibitors. Virology 255: 117–128.

    Article  CAS  PubMed  Google Scholar 

  • Esposti MD (2002). The roles of Bid. Apoptosis 7: 433–440.

    Article  CAS  PubMed  Google Scholar 

  • Friedlander RM (2003). Apoptosis and caspases in neurodegenerative diseases. N Engl J Med 348: 1365–1375.

    Article  CAS  PubMed  Google Scholar 

  • Fulda S, Meyer E, Friesen C, Susin SA, Kroemer G, Debatin KM (2001). Cell type specific involvement of death receptor and mitochondrial pathways in drug-induced apoptosis. Oncogene 20: 1063–1075.

    Article  CAS  PubMed  Google Scholar 

  • Gao CF, Ren S, Zhang L, Nakajima T, Ichinose S, Hara T, Koike K, Tsuchida N (2001). Caspase-dependent cytosolic release of cytochrome c and membrane translocation of Bax in p53-induced apoptosis. Exp Cell Res 265: 145–151.

    Article  CAS  PubMed  Google Scholar 

  • Gilbert GL, Dickson KE, Waters MJ, Kennett ML, Land SA, Sneddon M (1988). Outbreak of enterovirus 71 infection in Victoria, Australia, with a high incidence of neurologic involvement. Pediatr Infect Dis J 7: 484–488.

    Article  CAS  PubMed  Google Scholar 

  • Girard S, Couderc T, Destombes J, Thiesson D, Delpeyroux F, Blondel B (1999). Poliovirus induces apoptosis in the mouse central nervous system. J Virol 73: 6066–6072.

    CAS  PubMed  Google Scholar 

  • Goldstaub D, Gradi A, Bercovitch Z, Grosmann Z, Nophar Y, Luria S, Sonenberg N, Kahana C (2000). Poliovirus 2A protease induces apoptotic cell death. Mol Cell Biol 20: 1271–1277.

    Article  CAS  PubMed  Google Scholar 

  • Hayward JC, Gillespie SM, Kaplan KM, Packer R, Pallansch M, Plotkin S, Schonberger LB (1989). Outbreak of poliomyelitis-like paralysis associated with enterovirus 71. Pediatr Infect Dis J 8: 611–616.

    Article  CAS  PubMed  Google Scholar 

  • Heibein JA, Barry M, Motyka B, Bleackley RC (1999). Granzyme B-induced loss of mitochondrial inner membrane potential (Delta Psi m) and cytochrome c release are caspase independent. J Immunol 163: 4683–4693.

    CAS  PubMed  Google Scholar 

  • Herr I, Debatin KM (2001). Cellular stress response and apoptosis in cancer therapy. Blood 98: 2603–2614.

    Article  CAS  PubMed  Google Scholar 

  • Ho M (2000). Enterovirus 71: the virus, its infections and outbreaks. J Microbiol Immunol Infect 33: 205–216.

    CAS  PubMed  Google Scholar 

  • Ho M, Chen ER, Hsu KH, Twu SJ, Chen KT, Tsai SF, Wang JR, Shih SR (1999). An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med 341: 929–935.

    Article  CAS  PubMed  Google Scholar 

  • Holtzman MJ, Green JM, Jayaraman S, Arch RH (2000). Regulation of T cell apoptosis. Apoptosis 5: 459–471.

    Article  CAS  PubMed  Google Scholar 

  • Hsueh C, Jung SM, Shih SR, Kuo TT, Shieh WJ, Zaki S, Lin TY, Chang LY, Ning HC, Yen DC (2000). Acute encephalomyelitis during an outbreak of enterovirus type 71 infection in Taiwan: report of an autopsy case with pathologic, immunofluorescence, and molecular studies. Mod Pathol 13: 1200–1205.

    Article  CAS  PubMed  Google Scholar 

  • Huang CC, Liu CC, Chang YC, Chen CY, Wang ST, Yeh TF (1999). Neurologic complications in children with enterovirus 71 infection. N Engl J Med 341: 936–942.

    Article  CAS  PubMed  Google Scholar 

  • Huber SA, Budd RC, Rossner K, Newell MK (1999). Apoptosis in coxsackievirus B3-induced myocarditis and dilated cardiomyopathy. Ann N Y Acad Sci 887: 181–190.

    Article  CAS  PubMed  Google Scholar 

  • Jan JT, Chatterjee S, Griffin DE (2000). Sindbis virus entry into cells triggers apoptosis by activating sphingomyelinase, leading to the release of ceramide. J Virol 74: 6425–6432.

    Article  CAS  PubMed  Google Scholar 

  • Johnston C, Jiang W, Chu T, Levine B (2001). Identification of genes involved in the host response to neurovirulent alphavirus infection. J Virol 75: 10431–10445.

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann SH, Hengartner MO (2001). Programmed cell death: alive and well in the new millennium. Trends Cell Biol 11: 526–534.

    Article  CAS  PubMed  Google Scholar 

  • Kennett ML, Birch CJ, Lewis FA, Yung AP, Locarnini SA, Gust ID (1974). Enterovirus type 71 infection in Melbourne. Bull World Health Organ 51: 609–615.

    CAS  PubMed  Google Scholar 

  • Kuo RL, Kung SH, Hsu YY, Liu WT (2002). Infection with enterovirus 71 or expression of its 2A protease induces apoptotic cell death. J Gen Virol 83: 1367–1376.

    CAS  PubMed  Google Scholar 

  • Labrada L, Liang XH, Zheng W, Johnston C, Levine B (2002). Age-dependent resistance to lethal alphavirus encephalitis in mice: analysis of gene expression in the central nervous system and identification of a novel interferon-inducible protective gene, mouse ISG12. J Virol 76: 11688–11703.

    Article  CAS  PubMed  Google Scholar 

  • Lassus P, Opitz-Araya X, Lazebnik Y (2002). Requirement for caspase-2 in stress-induced apoptosis before mitochondrial permeabilization. Science 297: 1352–1354.

    Article  CAS  PubMed  Google Scholar 

  • Lewis J, Wesselingh SL, Griffin DE, Hardwick JM (1996). Alphavirus-induced apoptosis in mouse brains correlates with neurovirulence. J Virol 70: 1828–1835.

    CAS  PubMed  Google Scholar 

  • Li ML, Hsu TA, Chen TC, Chang SC, Lee JC, Chen CC, Stollar V, Shih SR (2002). The 3C protease activity of enterovirus 71 induces human neural cell apoptosis. Virology 293: 386–395.

    Article  CAS  PubMed  Google Scholar 

  • Lin TY, Chang LY, Hsia SH, Huang YC, Chiu CH, Hsueh C, Shih SR, Liu CC, Wu MH (2002). The 1998 enterovirus 71 outbreak in Taiwan: pathogenesis and management. Clin Infect Dis 34(Suppl 2): S52-S57.

    Article  PubMed  Google Scholar 

  • Lum LC, Wong KT, Lam SK, Chua KB, Goh AY, Lim WL, Ong BB, Paul G, AbuBakar S, Lambert M (1998). Fatal enterovirus 71 encephalomyelitis. J Pediatr 133: 795–798.

    Article  CAS  PubMed  Google Scholar 

  • Martelli AM, Zweyer M, Ochs RL, Tazzari PL, Tabellini G, Narducci P, Bortul R (2001). Nuclear apoptotic changes: an overview. J Cell Biochem 82: 634–646.

    Article  CAS  PubMed  Google Scholar 

  • Martin SJ, Matear PM, Vyakarnam A (1994). HIV-1 infection of human CD4+ T cells in vitro. Differential induction of apoptosis in these cells. J Immunol 152: 330–342.

    CAS  PubMed  Google Scholar 

  • McMinn P, Stratov I, Nagarajan L, Davis S (2001). Neurological manifestations of enterovirus 71 infection in children during an outbreak of hand, foot, and mouth disease in Western Australia. Clin Infect Dis 32: 236–242.

    Article  CAS  PubMed  Google Scholar 

  • Melcher A, Gough M, Todryk S, Vile R (1999). Apoptosis or necrosis for tumor immunotherapy: what’s in a name? J Mol Med 77: 824–833.

    Article  CAS  PubMed  Google Scholar 

  • Melnick JL (1984). Enterovirus type 71 infections: a varied clinical pattern sometimes mimicking paralytic poliomyelitis. Rev Infect Dis 6(Suppl 2): S387-S390.

    PubMed  Google Scholar 

  • Nagata N, Shimizu H, Ami Y, Tano Y, Harashima A, Suzaki Y, Sato Y, Miyamura T, Sata T, Iwasaki T (2002). Pyramidal and extrapyramidal involvement in experimental infection of cynomolgus monkeys with enterovirus 71. J Med Virol 67: 207–216.

    Article  PubMed  Google Scholar 

  • Nagy G, Takatsy S, Kukan E, Mihaly I, Domok I (1982). Virological diagnosis of enterovirus type 71 infections: experiences gained during an epidemic of acute CNS diseases in Hungary in 1978. Arch Virol 71: 217–227.

    Article  CAS  PubMed  Google Scholar 

  • Oberhaus SM, Smith RL, Clayton GH, Dermody TS, Tyler KL (1997). Reovirus infection and tissue injury in the mouse central nervous system are associated with apoptosis. J Virol 71: 2100–2106.

    CAS  PubMed  Google Scholar 

  • O’Brien V (1998). Viruses and apoptosis. J Gen Virol 79(Pt 8): 1833–1845.

    PubMed  Google Scholar 

  • Rao L, Perez D, White E (1996). Lamin proteolysis facilitates nuclear events during apoptosis. J Cell Biol 135: 1441–1455.

    Article  CAS  PubMed  Google Scholar 

  • Richardson-Burns SM, Kominsky DJ, Tyler KL (2002). Reovirus-induced neuronal apoptosis is mediated by caspase 3 and is associated with the activation of death receptors. J NeuroVirol 8: 365–380.

    Article  CAS  PubMed  Google Scholar 

  • Saraste A, Arola A, Vuorinen T, Kyto V, Kallajoki M, Pulkki K, Voipio-Pulkki LM, Hyypia T (2003). Cardiomyocyte apoptosis in experimental coxsackievirus B3 myocarditis. Cardiovasc Pathol 12: 255–262.

    Article  PubMed  Google Scholar 

  • Seet BT, Johnston JB, Brunetti CR, Barrett JW, Everett H, Cameron C, Sypula J, Nazarian SH, Lucas A, McFadden G (2003). Poxviruses and immune evasion. Annu Rev Immunol 21: 377–423.

    Article  CAS  PubMed  Google Scholar 

  • Shih SR, Ho MS, Lin KH, Wu SL, Chen YT, Wu CN, Lin TY, Chang LY, Tsao KC, Ning HC, Chang PY, Jung SM, Hsueh C, Chang KS (2000). Genetic analysis of enterovirus 71 isolated from fatal and non-fatal cases of hand, foot and mouth disease during an epidemic in Taiwan, 1998. Virus Res 68: 127–136.

    Article  CAS  PubMed  Google Scholar 

  • Shrestha B, Gottlieb D, Diamond MS (2003). Infection and injury of neurons by West Nile encephalitis virus. J Virol 77: 13203–13213.

    Article  CAS  PubMed  Google Scholar 

  • Teodoro JG, Branton PE (1997). Regulation of p53-dependent apoptosis, transcriptional repression, and cell transformation by phosphorylation of the 55-kilodalton E1B protein of human adenovirus type 5. J Virol 71: 3620–3627.

    CAS  PubMed  Google Scholar 

  • Theerasurakarn S, Ubol S (1998). Apoptosis induction in brain during the fixed strain of rabies virus infection correlates with onset and severity of illness. J NeuroVirol 4: 407–414.

    Article  CAS  PubMed  Google Scholar 

  • Ubol S, Park S, Budihardjo I, Desnoyers S, Montrose MH, Poirier GG, Kaufmann SH, Griffin DE (1996). Temporal changes in chromatin, intracellular calcium, and poly(ADP-ribose) polymerase during Sindbis virusinduced apoptosis of neuroblastoma cells. J Virol 70: 2215–2220.

    CAS  PubMed  Google Scholar 

  • Wen YY, Chang TY, Chen ST, Li C, Liu HS (2003). Comparative study of enterovirus 71 infection of human cell lines. J Med Virol 70: 109–118.

    Article  CAS  PubMed  Google Scholar 

  • Yu CK, Chen CC, Chen CL, Wang JR, Liu CC, Yan JJ, Su IJ (2000). Neutralizing antibody provided protection against enterovirus type 71 lethal challenge in neonatal mice. J Biomed Sci 7: 523–528.

    Article  CAS  PubMed  Google Scholar 

  • Zheng J, Thylin MR, Ghorpade A, Xiong H, Persidsky Y, Cotter R, Niemann D, Che M, Zeng YC, Gelbard HA, Shepard RB, Swartz JM, Gendelman HE (1999). Intracellular CXCR4 signaling, neuronal apoptosis and neuropathogenic mechanisms of HIV-1-associated dementia. J Neuroimmunol 98: 185–200.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Graduate Institute of Basic Medical Sciences, Chang Gung University, Tao-Yuan, Taiwan

    Shih-Cheng Chang, Jing-Yi Lin & Shin-Ru Shih

  2. School of Medical Technology, Chang Gung University, Tao-Yuan, Taiwan

    Shih-Cheng Chang, Jing-Yi Lin, Lily Yen-Cheng Lo, Mei-Ling Li & Shin-Ru Shih

  3. Clinical Virology Laboratory, Department of Clinical Pathology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

    Shin-Ru Shih

  4. Department of Molecular Genetics, Microbiology and Immunology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA

    Mei-Ling Li

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  1. Shih-Cheng Chang
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Chang, SC., Lin, JY., Lo, L.YC. et al. Diverse apoptotic pathways in enterovirus 71-infected cells. Journal of NeuroVirology 10, 338–349 (2004). https://doi.org/10.1080/13550280490521032

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