PDF(Pubmed)
Abstract：
The lack of disease models adequately resembling human tissue has hindered our understanding of amoebic brain infection. Three-dimensional structured organoids provide a microenvironment similar to human tissue. This study demonstrates the use of cerebral organoids to model a rare brain infection caused by the highly lethal amoeba Balamuthia mandrillaris. Cerebral organoids were generated from human pluripotent stem cells and infected with clinically isolated B. mandrillaris trophozoites. Histological examination showed amoebic invasion and neuron damage following coculture with the trophozoites. The transcript profile suggested an alteration in neuron growth and a proinflammatory response. The release of intracellular proteins specific to neuronal bodies and astrocytes was detected at higher levels postinfection. The amoebicidal effect of the repurposed drug nitroxoline was examined using the human cerebral organoids. Overall, the use of human cerebral organoids was important for understanding the mechanism of amoeba pathogenicity, identify biomarkers for brain injury, and in the testing of a potential amoebicidal drug in a context similar to the human brain.
摘要：
缺乏足够类似于人体组织的疾病模型阻碍了我们对阿米巴脑感染的理解。三维结构的类器官提供了类似于人体组织的微环境。这项研究证明了使用脑类器官来模拟由高度致命的变形虫Balamuthiamandrillaris引起的罕见脑感染。从人多能干细胞产生脑类器官,并用临床分离的曼肩芽孢杆菌滋养体感染。组织学检查显示，与滋养体共培养后，阿米巴入侵和神经元损伤。转录谱提示神经元生长和促炎反应的改变。感染后检测到较高水平的神经元体和星形胶质细胞特异性细胞内蛋白质的释放。使用人脑类器官检查了再利用的药物硝氧胆碱的杀变形虫作用。总的来说,人类大脑类器官的使用对于理解变形虫致病性的机制很重要，识别脑损伤的生物标志物，以及在类似于人脑的背景下测试潜在的杀变形虫药物。
