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Toxoplasma gondii excreted/secreted proteases disrupt intercellular junction proteins in epithelial cell monolayers to facilitate tachyzoites paracellular migration
Cellular Microbiology ( IF 3.4 ) Pub Date : 2020-10-27 , DOI: 10.1111/cmi.13283
Carlos J Ramírez-Flores 1 , Rosalba Cruz-Mirón 1 , Noé Lagunas-Cortés 1 , Mónica Mondragón-Castelán 1 , Ricardo Mondragon-Gonzalez 2 , Sirenia González-Pozos 3 , Ricardo Mondragón-Flores 1
Affiliation  

Toxoplasma gondii shows high dissemination and migration properties across biological barriers infecting immunologically privileged organs. Toxoplasma uses different routes for dissemination; however, the mechanisms are not fully understood. Herein, we studied the effects of proteases present in excretion/secretion products (ESPs) of Toxoplasma on MDCK cell monolayers. Ultrastructural analysis showed that ESPs of Toxoplasma disrupt the intercellular junctions (IJ) of adjacent cells. The tight junction (TJ) proteins ZO‐1, occludin, and claudin‐1 suffered a progressive decrease in protein levels upon ESPs treatment. In addition, ESPs induced mislocalization of such TJ proteins, along with the adherent junction protein E‐cadherin, and this was prevented by pre‐treating the ESPs with protease inhibitors. Reorganisation of cytoskeleton proteins was also observed. Endocytosis inhibitors, Dyngo®‐4a and Dynasore, impeded the modifications, suggesting that TJ proteins internalisation is triggered by the ESPs proteases hence contributing to the loss of IJ. The observed disruption in TJ proteins went in line with a decrease in the transepithelial electrical resistance of the monolayers, which was significantly blocked by pre‐treating ESPs with metalloprotease and serine protease inhibitors. Moreover, exposure of cell monolayers to ESPs facilitated paracellular migration of tachyzoites. Our results demonstrate that Toxoplasma ESPs contain proteases that can disrupt the IJ of epithelial monolayers and this could facilitate the paracellular route for Toxoplasma tissue dissemination and migration.

中文翻译:

弓形虫分泌/分泌的蛋白酶破坏上皮细胞单层中的细胞间连接蛋白,以促进速殖子细胞旁迁移

弓形虫表现出跨越感染免疫特权器官的生物屏障的高度传播和迁移特性。弓形虫使用不同的传播途径;然而,尚未完全了解这些机制。在此,我们研究了弓形虫的排泄/分泌产物 (ESP) 中存在的蛋白酶对 MDCK 细胞单层的影响。超微结构分析表明弓形虫的ESPs破坏相邻细胞的细胞间连接 (IJ)。在 ESP 处理后,紧密连接 (TJ) 蛋白 ZO-1、occludin 和 claudin-1 的蛋白质水平逐渐降低。此外,ESP 会诱导此类 TJ 蛋白以及粘附连接蛋白 E-钙粘蛋白的错误定位,这可以通过用蛋白酶抑制剂预处理 ESP 来防止。还观察到细胞骨架蛋白的重组。内吞抑制剂 Dyngo®-4a 和 Dynasore 阻碍了修饰,表明 TJ 蛋白内化是由 ESP 蛋白酶触发的,因此导致 IJ 的丧失。观察到的 TJ 蛋白破坏与单层跨上皮电阻的降低一致,用金属蛋白酶和丝氨酸蛋白酶抑制剂预处理 ESP 可显着阻断。此外,细胞单层暴露于 ESP 促进了速殖子的细胞旁迁移。我们的结果表明弓形虫ESP 含有蛋白酶,可以破坏上皮单层的 IJ,这可以促进弓形虫组织传播和迁移的细胞旁途径。
更新日期:2020-10-27
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