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Toxoplasma gondii induce apoptosis of neural stem cells via endoplasmic reticulum stress pathway

  • TENG WANG (a1), JIE ZHOU (a1), XIAOFENG GAN (a1), HUA WANG (a1) (a2), XIAOJUAN DING (a1), LINGZHI CHEN (a1), YONGZHONG WANG (a3) (a4), JIAN DU (a5), JILONG SHEN (a1) and LI YU (a1)...


Toxoplasma gondii is a major cause of congenital brain disease; however, the underlying mechanism of neuropathogenesis in brain toxoplasmosis remains elusive. To explore the role of T. gondii in the development of neural stem cells (NSCs), NSCs were isolated from GD14 embryos of ICR mice and were co-cultured with tachyzoites of T. gondii RH strain. We found that apoptosis levels of the NSCs co-cultured with 1×106 RH tachyzoites for 24 and 48 h significantly increased in a dose-dependent manner, as compared with the control. Western blotting analysis displayed that the protein level of C/EBP homologous protein (CHOP) was up-regulated, and caspase-12 and c-Jun N-terminal kinase (JNK) were activated in the NSCs co-cultured with the parasites. Pretreatment with endoplasmic reticulum stress (ERS) inhibitor (TUDCA) and caspase-12 inhibitor (Z-ATAD-FMK) inhibited the expression or activation of the key molecules involved in the ERS-mediated apoptotic pathway, and subsequently decreased the apoptosis levels of the NSCs induced by the T. gondii. The findings here highlight that T. gondii induced apoptosis of the NSCs through the ERS signal pathway via activation of CHOP, caspase-12 and JNK, which may constitute a potential molecular mechanism responsible for the cognitive disturbance in neurological disorders of T. gondii.


Corresponding author

* Corresponding author: Department of Microbiology and Parasitology, Anhui Medical University, Hefei 230032, China. E-mail:


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Allen, J. R., Nguyen, L. X., Sargent, K. E., Lipson, K. L., Hackett, A. and Urano, F. (2004). High ER stress in beta-cells stimulates intracellular degradation of misfolded insulin. Biochemical and Biophysical Research Communications 324, 166170. doi:10.1016/j.bbrc.2004.09.035.
Amano, T., Yamasaki, S., Yagishita, N., Tsuchimochi, K., Shin, H., Kawahara, K., Aratani, S., Fujita, H., Zhang, L., Ikeda, R., Fujii, R., Miura, N., Komiya, S., Nishioka, K., Maruyama, I., Fukamizu, A. and Nakajima, T. (2003). Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy. Genes and Development 17, 24362449. doi:10.1101/gad.1096603.
Andreoletti, O., Budka, H., Buncic, S., Colin, P., Collins, D. J., Koeijer, A. D., Griffin, J., Havelaar, A., Hope, J., Klein, G., Kruse, H., Magnino, S., López, A. M., McLauchlin, J., Nguyen-Thé, C., Noeckler, K., Noerrung, B., Maradona, M. P., Roberts, T., Vågsholm, I. and Vanopdenbosch, E. (2007). Scientific opinion of the Panel on Biological Hazards on a request from EFSA on surveillance and monitoring of Toxoplasma in humans, foods and animals. EFSA Journal 583, 164.
Araki, E., Oyadomari, S. and Mori, M. (2003). Endoplasmic reticulum stress and diabetes mellitus. Internal Medicine 42, 714. doi:10.2169/internalmedicine.42.7.
Carmen, J. C. and Sinai, A. P. (2007). Suicide prevention: disruption of apoptotic pathways by protozoan parasites. Molecular Microbiology 64, 904916. doi:10.1111/j.1365-2958.2007.05714.x.
Contreras-Ochoa, C. O., Lagunas-Martinez, A., Belkind-Gerson, J., Diaz-Chavez, J. and Correa, D. (2013). Toxoplasma gondii invasion and replication within neonate mouse astrocytes and changes in apoptosis related molecules. Experimental Parasitology 134, 256265. doi:10.1016/j.exppara.2013.03.010.
D'Aiuto, L., Di Maio, R., Heath, B., Raimondi, G., Milosevic, J., Watson, A. M., Bamne, M., Parks, W. T., Yang, L., Lin, B., Miki, T., Mich-Basso, J. D., Arav-Boger, R., Sibille, E., Sabunciyan, S., Yolken, R. and Nimgaonkar, V. (2012). Human induced pluripotent stem cell-derived models to investigate human cytomegalovirus infection in neural cells. PLoS One 7, e49700. doi:10.1371/journal.pone.0049700.
Das, S. and Basu, A. (2008). Japanese encephalitis virus infects neural progenitor cells and decreases their proliferation. Journal of Neurochemistry 106, 16241636. doi:10.1111/j.1471-4159.2008.05511.x.
Dubey, J. P. (2010). Toxoplasmosis of Animals and Humans, 2nd Edn. CRC Press, Boca Raton, FL, USA.
el-Sagaff, S., Salem, H. S., Nichols, W., Tonkel, A. K. and Abo-Zenadah, N. Y. (2005). Cell death pattern in cerebellum neurons infected with Toxoplasma gondii . Journal of the Egyptian Society of Parasitology 35, 809818.
Fang, Y., Yu, S., Ellis, J. S., Sharav, T. and Braley-Mullen, H. (2010). Comparison of sensitivity of Th1, Th2, and Th17 cells to Fas-mediated apoptosis. Journal of Leukocyte Biology 87, 10191028. doi:10.1189/jlb.0509352.
Gao, B., Lee, S. M., Chen, A., Zhang, J., Zhang, D. D., Kannan, K., Ortmann, R. A. and Fang, D. (2008). Synoviolin promotes IRE1 ubiquitination and degradation in synovial fibroblasts from mice with collagen-induced arthritis. EMBO Reports 9, 480485. doi:10.1038/embor.2008.37.
Grant, I. H., Gold, J. W., Rosenblum, M., Niedzwiecki, D. and Armstrong, D. (1990). Toxoplasma gondii serology in HIV-infected patients: the development of central nervous system toxoplasmosis in AIDS. Aids 4, 519521.
Hermanns, B., Brunn, A., Schwarz, E. R., Sachweh, J. S., Seipelt, I., Schroder, J. M., Vogel, U., Schoendube, F. A. and Buettner, R. (2001). Fulminant toxoplasmosis in a heart transplant recipient. Pathology, Research and Practice 197, 211215.
Hill, D. and Dubey, J. P. (2002). Toxoplasma gondii: transmission, diagnosis and prevention. Clinical Microbiology and Infection 8, 634640. doi:10.1046/j.1469-0691.2002.00485.x.
Joseph, B. and Hermanson, O. (2010). Molecular control of brain size: regulators of neural stem cell life, death and beyond. Experimental Cell Research 316, 14151421. doi:10.1016/j.yexcr.2010.03.012.
Kaufman, R. J., Scheuner, D., Schroder, M., Shen, X., Lee, K., Liu, C. Y. and Arnold, S. M. (2002). The unfolded protein response in nutrient sensing and differentiation. Nature Reviews. Molecular Cell Biology 3, 411421. doi:10.1038/nrm829.
Laliberte, J. and Carruthers, V. B. (2008). Host cell manipulation by the human pathogen Toxoplasma gondii . Cellular and Molecular Life Sciences: CMLS 65, 19001915. doi:10.1007/s00018-008-7556-x.
Lei, X., Zhang, S., Barbour, S. E., Bohrer, A., Ford, E. L., Koizumi, A., Papa, F. R. and Ramanadham, S. (2010). Spontaneous development of endoplasmic reticulum stress that can lead to diabetes mellitus is associated with higher calcium-independent phospholipase A2 expression: a role for regulation by SREBP-1. Journal of Biological Chemistry 285, 66936705. doi:10.1074/jbc.M109.084293.
Li, R. Y., Kosugi, I. and Tsutsui, Y. (2004). Activation of murine cytomegalovirus immediate-early promoter in mouse brain after transplantation of the neural stem cells. Acta Neuropathologica 107, 406412. doi:10.1007/s00401-004-0828-0.
Merkle, F. T. and Alvarez-Buylla, A. (2006). Neural stem cells in mammalian development. Current Opinion in Cell Biology 18, 704709. doi:10.1016/
Mordue, D. G., Monroy, F., La Regina, M., Dinarello, C. A. and Sibley, L. D. (2001). Acute toxoplasmosis leads to lethal overproduction of Th1 cytokines. Journal of Immunology 167, 45744584.
Mutnal, M. B., Cheeran, M. C., Hu, S. and Lokensgard, J. R. (2011). Murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain. PLoS One 6, e16211. doi:10.1371/journal.pone.0016211.
Nadav, E., Shmueli, A., Barr, H., Gonen, H., Ciechanover, A. and Reiss, Y. (2003). A novel mammalian endoplasmic reticulum ubiquitin ligase homologous to the yeast Hrd1. Biochemical and Biophysical Research Communications 303, 9197. doi: S0006291X03002791.
Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B. A. and Yuan, J. (2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403, 98103. doi: 10.1038/47513.
Nash, P. B., Purner, M. B., Leon, R. P., Clarke, P., Duke, R. C. and Curiel, T. J. (1998). Toxoplasma gondii infected cells are resistant to multiple inducers of apoptosis. Journal of Immunology 160, 18241830.
Nishikawa, Y., Kawase, O., Vielemeyer, O., Suzuki, H., Joiner, K. A., Xuan, X. and Nagasawa, H. (2007). Toxoplasma gondii infection induces apoptosis in noninfected macrophages: role of nitric oxide and other soluble factors. Parasite Immunology 29, 375385. doi:10.1111/j.1365-3024.2007.00956.x.
Odeberg, J., Wolmer, N., Falci, S., Westgren, M., Seiger, A. and Soderberg-Naucler, C. (2006). Human cytomegalovirus inhibits neuronal differentiation and induces apoptosis in human neural precursor cells. Journal of Virology 80, 89298939. doi: 10.1128/JVI.00676-06.
Oyadomari, S., Takeda, K., Takiguchi, M., Gotoh, T., Matsumoto, M., Wada, I., Akira, S., Araki, E. and Mori, M. (2001). Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proceedings of the National Academy of Sciences USA 98, 1084510850. doi: 10.1073/pnas.191207498.
Oyadomari, S., Koizumi, A., Takeda, K., Gotoh, T., Akira, S., Araki, E. and Mori, M. (2002). Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. Journal of Clinical Investigation 109, 525532. doi: 10.1172/JCI14550.
Petersen, E. (2007). Toxoplasmosis. Seminars in Fetal & Neonatal Medicine 12, 214223.
Ponticelli, C. and Campise, M. R. (2005). Neurological complications in kidney transplant recipients. Journal of Nephrology 18, 521528.
Ron, D. and Habener, J. F. (1992). CHOP, a novel developmentally regulated nuclear protein that dimerizes with transcription factors C/EBP and LAP and functions as a dominant-negative inhibitor of gene transcription. Genes and Development 6, 439453.
Sun, T., Wang, X. J., Xie, S. S., Zhang, D. L., Wang, X. P., Li, B. Q., Ma, W. and Xin, H. (2011). A comparison of proliferative capacity and passaging potential between neural stem and progenitor cells in adherent and neurosphere cultures. International Journal of Developmental Neuroscience 29, 723731. doi: 10.1016/j.ijdevneu.2011.05.012.
Sun, X., Guan, Y., Li, F., Li, X., Wang, X., Guan, Z., Sheng, K., Yu, L. and Liu, Z. (2012). Effects of rat cytomegalovirus on the nervous system of the early rat embryo. Virologica Sinica 27, 234240. doi: 10.1007/s12250-012-3250-0.
Takahashi, J., Fukuda, T., Tanaka, J., Minamitani, M., Onouchi, K. and Makioka, A. (2001). Bax-induced apoptosis not demonstrated in the congenital toxoplasmosis in mice. Brain & Development 23, 5053. doi:10.1016/S0387-7604(01)00179-6.
Tenter, A. M., Heckeroth, A. R. and Weiss, L. M. (2000). Toxoplasma gondii: from animals to humans. International Journal for Parasitology 30, 12171258. doi: S0020-7519(00)00124-7.
Tsutsui, Y., Kosugi, I. and Kawasaki, H. (2005). Neuropathogenesis in cytomegalovirus infection: indication of the mechanisms using mouse models. Reviews in Medical Virology 15, 327345. doi: 10.1002/rmv.475.
Urano, F., Wang, X., Bertolotti, A., Zhang, Y., Chung, P., Harding, H. P. and Ron, D. (2000). Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287, 664666. doi: 10.1126/science.287.5453.664.
Wang, X. Z., Lawson, B., Brewer, J. W., Zinszner, H., Sanjay, A., Mi, L. J., Boorstein, R., Kreibich, G., Hendershot, L. M. and Ron, D. (1996). Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Molecular and Cellular Biology 16, 42734280.
Zinszner, H., Kuroda, M., Wang, X., Batchvarova, N., Lightfoot, R. T., Remotti, H., Stevens, J. L. and Ron, D. (1998). CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes and Development 12, 982995.



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