Hashino Masanori, Tachibana Masato, Nishida Takashi, Hara Hideki, Tsuchiya Kohsuke, Mitsuyama Masao, Watanabe Kenta, Shimizu Takashi, Watarai Masahisa
The United Graduate School of Veterinary Science, Yamaguchi University, Yoshida Campus Yamaguchi, Japan.
The United Graduate School of Veterinary Science, Yamaguchi University, Yoshida Campus Yamaguchi, Japan ; Division of Biomedical Food Research, National Institute of Health Sciences Tokyo, Japan.
Front Microbiol. 2015 Oct 16;6:1145. doi: 10.3389/fmicb.2015.01145. eCollection 2015.
Listeria monocytogenes has a well-characterized ability to cross the placental barrier, resulting in spontaneous abortion and fetal infections. However, the mechanisms resulting in infection-associated abortion are not fully understood. In this study, we demonstrate that the dephosphorylation of MAPK family proteins caused by L. monocytogenes infection of trophoblast giant (TG) cells, which are placental immune cells, contributes to infectious abortion. Dephosphorylation of c-Jun, p38, and ERK1/2 was observed in infected TG cells, causing the downregulation of cytoprotective heme oxygenase (HO)-1. Blocking the dephosphorylation of proteins, including MAPK family proteins, inhibited the decrease in HO-1 expression. Treatment with MAPK inhibitors inhibited bacterial internalization into TG cells. Moreover, Toll-like receptor 2 involved in the expression of MAPK family proteins. Infection with a listeriolysin O-deleted mutant impaired dephosphorylation of MAPK family proteins in TG cells and did not induce infectious abortion in a mouse model. These results suggest that inactivation of the MAPK pathway by L. monocytogenes induces TG cell death and causes infectious abortion.
单核细胞增生李斯特菌具有穿越胎盘屏障的明确能力，可导致自然流产和胎儿感染。然而，导致感染相关流产的机制尚未完全明确。在本研究中，我们证明，作为胎盘免疫细胞的滋养层巨细胞（TG）受单核细胞增生李斯特菌感染后，丝裂原活化蛋白激酶（MAPK）家族蛋白的去磷酸化作用会导致感染性流产。在受感染的TG细胞中观察到c-Jun、p38和ERK1/2的去磷酸化，导致细胞保护性血红素加氧酶（HO）-1表达下调。阻断包括MAPK家族蛋白在内的蛋白质的去磷酸化作用，可抑制HO-1表达的降低。用MAPK抑制剂处理可抑制细菌内化进入TG细胞。此外，Toll样受体2参与MAPK家族蛋白的表达。用缺失溶血素O的突变体感染会损害TG细胞中MAPK家族蛋白的去磷酸化作用，并且不会在小鼠模型中诱导感染性流产。这些结果表明，单核细胞增生李斯特菌使MAPK通路失活会诱导TG细胞死亡并导致感染性流产。
