Department of Infectious Diseases and Host Defense, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Laboratory of Metabolic Signal, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
Int J Parasitol. 2020 Dec;50(14):1167-1175. doi: 10.1016/j.ijpara.2020.07.007. Epub 2020 Sep 1.
Cerebral malaria is one of the most severe pathologies of malaria; it induces neuro-cognitive sequelae and has a high mortality rate. Although many factors involved in the development of cerebral malaria have been discovered, its pathogenic mechanisms are still not completely understood. Most studies on cerebral malaria have focused on the blood-brain barrier, despite the importance of the blood-cerebrospinal fluid barrier, which protects the brain from peripheral inflammation. Consequently, the pathological role of the blood-cerebrospinal fluid barrier in cerebral malaria is currently unknown. To examine the status of the blood-cerebrospinal fluid barrier in cerebral malaria and malaria without this pathology (non-cerebral malaria), we developed a new method for evaluating the permeabilization of the blood-cerebrospinal fluid barrier during cerebral malaria in mice, using Evans blue dye and a software-assisted image analysis. Using C57BL/6J (B6) mice infected with Plasmodium berghei ANKA strain as an experimental cerebral malaria model and B6 mice infected with P. berghei NK65 strain or Plasmodium yoelii as non-cerebral malaria models, we revealed that the permeability of the blood-cerebrospinal fluid barrier increased during experimental cerebral malaria but not during non-cerebral malaria. We observed haemorrhaging in the cerebral ventricles and hemozoin-like structures in the choroid plexus, which is a key component of the blood-cerebrospinal fluid barrier, in cerebral malaria mice. Taken together, this evidence indicates that the blood-cerebrospinal fluid barrier is disrupted in experimental cerebral malaria, whereas it remains intact in non-cerebral malaria. We also found that P. berghei ANKA parasites and CD8 T cells are involved in the blood-cerebrospinal fluid barrier disruption in experimental cerebral malaria. An understanding of the mechanisms underlying cerebral malaria might help in the development of effective strategies to prevent and manage cerebral malaria in humans.
脑型疟疾是疟疾最严重的病理类型之一；它会引起神经认知后遗症，并且死亡率很高。尽管已经发现了许多与脑型疟疾发展相关的因素，但它的发病机制仍不完全清楚。尽管血脑屏障对保护大脑免受外周炎症至关重要，但大多数脑型疟疾的研究都集中在血脑屏障上。因此，血脑脊液屏障在脑型疟疾中的病理作用目前尚不清楚。为了研究脑型疟疾和无此病理（非脑型疟疾）中血脑脊液屏障的状态，我们开发了一种新方法，用于评估在脑型疟疾小鼠中血脑脊液屏障的通透性，使用 Evans 蓝染料和软件辅助图像分析。我们使用 Plasmodium berghei ANKA 株感染的 C57BL/6J（B6）小鼠作为实验性脑型疟疾模型，并用 P. berghei NK65 株或 Plasmodium yoelii 感染的 B6 小鼠作为非脑型疟疾模型，结果表明，在实验性脑型疟疾期间血脑脊液屏障的通透性增加，但在非脑型疟疾期间没有增加。我们观察到脑型疟疾小鼠的脑室内有出血和脉络丛中有血铁红素样结构，这是血脑脊液屏障的关键组成部分。总之，这些证据表明，在实验性脑型疟疾中血脑脊液屏障被破坏，而非脑型疟疾中血脑脊液屏障保持完整。我们还发现 P. berghei ANKA 寄生虫和 CD8 T 细胞参与了实验性脑型疟疾中的血脑脊液屏障破坏。对脑型疟疾发病机制的了解可能有助于开发预防和治疗人类脑型疟疾的有效策略。
