ROS-triggered trophoblast apoptosis is initiated by ER stress via activation of caspase12, CHOP and the JNK pathway in Toxoplasma gondii infection

Infect Immun. 2012 Apr 2. [Epub ahead of print]

ROS-triggered trophoblast apoptosis is initiated by ER stress via activation of caspase12, CHOP and the JNK pathway in Toxoplasma gondii infection in mice.

Xu X, Liu T, Zhang A, Huo X, Luo Q, Chen Z, Yu L, Li Q, Liu L, Lun Z, Shen J.

SourceAnhui Provincial Laboratories of Pathogen Biology and Zoonoses; Department of Microbiology and Parasitology, Anhui Medical University, Hefei, China.

Abstract
Toxoplasma gondii infection in pregnant women may result in abortion or in fetal teratogenesis; however, the underlying mechanisms are still unclear. In this paper, based on a murine model, we showed that maternal infection with RH-strain T. gondii tachyzoites induced elevated production of reactive oxygen species (ROS), local oxidative stress and subsequent apoptosis of placental trophoblasts. PCR Array analysis of 84 oxidative stress-related genes demonstrated that twenty-seven genes were up-regulated at least 2-fold and that nine genes were down-regulated at least 2-fold in the T.gondii infection group, compared with the control group. The expression of NADPH oxidase 1(Nox1) and glutathione peroxidase 6 (Gpx6) increased significantly, about 25-fold. The levels of malondialdehyde (MDA) and 8-OHdG increased significantly with T. gondii infection, and levels of glutathione (GSH) decreased rapidly. T. gondii infection increased the early expression of endoplasmic reticulum stress(ERS)markers, followed by cleavage of caspase-12, activation of ASK1/JNK and increased apoptosis of trophoblasts, both in vivo and in vitro. The apoptosis of trophoblasts, the activation of caspase-12 and the ASK1/JNK pathway and the production of peroxides were dramatically inhibited by pretreatment with N-acetylcysteine (NAC). The up-regulation of Nox1 was contact-dependent and preceded the increase in levels of ERS markers and the activation of the pro-apoptosis cascade. Thus, we concluded that apoptosis in placental trophoblasts was initiated predominantly by ROS-mediated ERS via activation of caspase12, CHOP and the JNK pathway in acute T. gondii infection. Elevated ROS production is the central event in T. gondii-induced apoptosis of placental trophoblasts.

PMID: 22473610 [PubMed - as supplied by publisher]