Transcriptome Profiling ofToxoplasma gondii-Infected Human Cerebromicrovascular Endothelial Cell Response to Treatment with Monensin

文献类型： 外文期刊

第一作者： Harun, Mohammad S. R.

作者： Harun, Mohammad S. R.;Taylor, Mica;Elsheikha, Hany M.;Zhu, Xing-Quan

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关键词： Toxoplasma gondii; monensin; TEER; gene expression; Wnt signaling

期刊名称：MICROORGANISMS （ 影响因子：4.128； ）

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年卷期： 2020 年 8 卷 6 期

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收录情况： SCI

摘要： Central to the progression of cerebral toxoplasmosis is the interaction ofToxoplasma gondiiwith the blood-brain barrier (BBB) endothelial cells. In the present work, we tested the hypothesis that inhibition of Wnt pathway signalling by the monovalent ionophore monensin reduces the growth ofT. gondiiinfecting human brain microvascular endothelial cells (hBMECs) or microglial cells. The anti-parasitic effect of monensin (a Wnt signalling inhibitor) on the in vitro growth ofT. gondiitachyzoites was investigated using two methods (Sulforhodamine B staining and microscopic parasite counting). The monensin inhibitedT. gondiigrowth (50% inhibitory concentration [IC50] = 0.61 mu M) with a selective index = 8.48 when tested against hBMECs (50% cytotoxic concentration [CC50] = 5.17 mu M). However, IC(50)of monensin was 4.13 mu M with a SI = 13.82 when tested against microglia cells (CC50= 57.08 mu M), suggesting less sensitivity of microglia cells to monensin treatment. The effect ofT. gondiion the integrity of the BBB was assessed by the transendothelial electrical resistance (TEER) assay using an in vitro human BBB model. The results showed thatT. gondiiinfection significantly decreased hBMECs' TEER resistance, which was rescued when cells were treated with 0.1 mu M monensin, probably due to the anti-parasitic activity of monensin. We also investigated the host-targeted effects of 0.1 mu M monensin on global gene expression in hBMECs with or withoutT. gondiiinfection. Treatment of hBMECs with monensin did not significantly influence the expression of genes involved in the Wnt signalling pathway, suggesting that although inhibition of the Wnt signalling pathway did not play a significant role inT. gondiiinfection of hBMECs, monensin was still effective in limiting the growth ofT. gondii. On the contrary, monensin treatment downregulated pathways related to steroids, cholesterol and protein biosynthesis and their transport between endoplasmic reticulum and Golgi apparatus, and deregulated pathways related to cell cycle and DNA synthesis and repair mechanisms. These results provide new insight into the host-modulatory effect of monensin duringT. gondiiinfection, which merits further investigation.

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