Toxoplasma gondiiinduce apoptosis of neural stem cells via endoplasmic reticulum stress pathway

Abstract

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.

Rottlerin-mediated inhibition of Toxoplasma gondii growth in BeWo trophoblast-like cells

“…It is very possible that this tight interaction could led to ER stress and trigger the so called unfolding protein response in the host. Consistently, recent studies reported that apoptosis of mice trophoblasts and neural stem cells infected with T. gondii was triggered by ER stress 41, 42 . Although no (apoptotic) death was observed in infected BeWo cells, the results from Western blotting analysis of cell lysates after infection showed increased eIF2α phosphorylation, indicating the activation of the ER stress-stimulated kinase, PERK.…”

Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes?

“…Consistently, recent evidence indicates that apoptosis of placental trophoblasts and neural stem cells infected with T. gondii involves activation of ER stress pathways 125,126 , via induction of CHOP, caspase 12 and the JNK pathway. Trophoblast apoptosis is initiated by oxidative stress following reactive oxygen species (ROS) production, while cell death stimuli in neural stem cells are unknown, yet these findings highlight a UPR response to T. gondii infection.…”

Toxoplasma gondii inhibits differentiation of C17.2 neural stem cells through Wnt/β-catenin signaling pathway

“…Our previous data showed the parasite was able to invade NSCs isolated from GD14 embryos of ICR mice and the C17.2 NSCs, inducing apparent apoptosis of these NSCs. TgESAs induced-apoptosis in NSCs partly explained a possible mechanism of brain pathological damages caused by congenital T. gondii infection [12,13]. However, whether the parasite disturbs the normal differentiation of NSCs as that happened to HCMV is still unknown.…”

“…T. gondii has the widest range of host cells, showing sophisticated capability for invading almost all nucleated cells of warm-blooded animals, such as the NSCs in mammals. In our previous study, we found that the parasites was able to invade the NSCs and their excreted-secreted antigens (ESAs) induced apoptosis of the NSCs through endoplasmic reticulum stress (ERS) signaling pathways [12,13]. To further elucidate the molecular mechanisms underlying the neuropathogenesis in congenital toxoplasmosis, this study aims to evaluate the effects of the ESAs of T. gondii (Tg-ESAs) on differentiation capability of NSCs into neurons or astrocytes and assess the involvement of Wnt/b-catenin signaling pathway, especially the role of b-catenin, in the blockade of differentiation of C17.2 NSCs induced by the Tg-ESAs.…”