School of Pharmacy, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1300 South Coulter Street, Amarillo, TX, 79106, USA.
Mycotoxin Res. 2018 Nov;34(4):257-268. doi: 10.1007/s12550-018-0320-7. Epub 2018 Jul 13.
Cerebral fungal infections represent an important public health concern, where a key element of pathophysiology is the ability of the fungi to cross the blood-brain barrier (BBB). Yet the mechanism used by micro-organisms to cross such a barrier and invade the brain parenchyma remains unclear. This study investigated the effects of gliotoxin (GTX), a mycotoxin secreted by Aspergillus fumigatus, on the BBB using brain microvascular endothelial cells (BMECs) derived from induced pluripotent stem cells (iPSCs). We observed that both acute (2 h) and prolonged (24 h) exposure to GTX at the level of 1 μM or higher compromised BMECs monolayer integrity. Notably, acute exposure was sufficient to disrupt the barrier function in iPSC-derived BMECs, resulting in decreased transendothelial electrical resistance (TEER) and increased fluorescein permeability. Further, our data suggest that such disruption occurred without affecting tight junction complexes, via alteration of cell-matrix interactions, alterations in F-actin distribution, through a protein kinase C-independent signaling. In addition to its effect on the barrier function, we have observed a low permeability of GTX across the BBB. This fact can be partially explained by possible interactions of GTX with membrane proteins. Taken together, this study suggests that GTX may contribute in cerebral invasion processes of Aspergillus fumigatus by altering the blood-brain barrier integrity without disrupting tight junction complexes.
脑真菌感染是一个重要的公共卫生关注点，其中一个关键的病理生理学要素是真菌穿过血脑屏障 (BBB) 的能力。然而，微生物用于穿过这种屏障并侵入脑实质的机制尚不清楚。本研究使用源自诱导多能干细胞 (iPSC) 的脑微血管内皮细胞 (BMEC) 研究了曲霉菌分泌的霉菌毒素Gliotoxin (GTX) 对 BBB 的影响。我们观察到，在 1μM 或更高水平下，无论是急性 (2 小时) 还是长期 (24 小时) 暴露于 GTX，都会损害 BMEC 单层的完整性。值得注意的是，急性暴露足以破坏 iPSC 衍生的 BMEC 中的屏障功能，导致跨内皮电阻 (TEER) 降低和荧光素通透性增加。此外，我们的数据表明，这种破坏是通过改变细胞-基质相互作用、F-肌动蛋白分布的改变以及蛋白激酶 C 非依赖性信号传导而不影响紧密连接复合物来发生的。除了对屏障功能的影响外，我们还观察到 GTX 穿过 BBB 的低通透性。这一事实可以部分解释为 GTX 与膜蛋白的可能相互作用。总之，本研究表明，GTX 可能通过改变血脑屏障的完整性而不破坏紧密连接复合物，从而有助于烟曲霉菌的大脑入侵过程。
