Schmidt S, Schwerk C, Schroten H, Ishikawa H, Schubert R, Lehrnbecher T, Rudolph H
Department of Pediatrics, Division of Hematology, Oncology and Hemostaseology, Goethe University Frankfurt, Frankfurt/Main, Germany.
Pediatric Infectious Diseases, Medical Faculty Mannheim, University Children's Hospital Mannheim, Heidelberg University, Mannheim, Germany.
Fluids Barriers CNS. 2025 Apr 4;22(1):34. doi: 10.1186/s12987-025-00644-x.
Despite the availability of potent antifungal compounds, invasive fungal disease poses significant morbidity and mortality in immunocompromised patients. Candida albicans is one of the leading pathogens in this setting, and may affect the central nervous system (CNS), which is an extremely severe form of the infection. As the exact pathogenesis of Candida CNS infection is not clear, we investigated the mechanisms and effects of C. albicans transmigration into the CNS, which will be helpful for diagnosis, prevention and treatment.
We used a human in vitro model of the Blood-Cerebrospinal Fluid Barrier (BCSFB), and we investigated the mechanisms of Candida albicans translocation into the CNS. Translocation was evaluated using immunofluorescence analysis focusing on tight and adherens junctions and the actin cytoskeleton. Barrier integrity was monitored via measurement of transepithelial resistance and the paracellular permeability of dextran. LIVE/DEAD assays were applied for viability controls and a cytometric bead array was performed to detect cytokine secretion of plexus epithelial cells.
Translocation at low doses occurs transcellularly in the absence of cytotoxicity or secretion of proinflammatory cytokines. This is accomplished by the formation of a tunnel-like structure exploiting the actin cytoskeleton. With higher infection doses of Candida albicans, a reduction in barrier integrity due to disruption of tight and adherens junctions was observed and cytotoxicity also increased.
Our findings reveal that Candida albicans can use transcellular translocation to invade into the CNS and is able to circumvent major host immune response, which may impact on diagnostic and preventive strategies.
尽管有强效抗真菌化合物，但侵袭性真菌病在免疫功能低下的患者中仍会导致显著的发病率和死亡率。白色念珠菌是这种情况下的主要病原体之一，可能会影响中枢神经系统（CNS），这是一种极其严重的感染形式。由于白色念珠菌中枢神经系统感染的确切发病机制尚不清楚，我们研究了白色念珠菌迁移至中枢神经系统的机制和影响，这将有助于诊断、预防和治疗。
我们使用了血脑脊髓液屏障（BCSFB）的人体体外模型，研究白色念珠菌迁移至中枢神经系统的机制。通过聚焦紧密连接、黏附连接和肌动蛋白细胞骨架的免疫荧光分析来评估迁移情况。通过测量跨上皮电阻和葡聚糖的细胞旁通透性来监测屏障完整性。应用活/死检测进行生存能力对照，并进行细胞计数珠阵列检测丛上皮细胞的细胞因子分泌。
低剂量时的迁移通过利用肌动蛋白细胞骨架形成隧道样结构以跨细胞方式发生，且无细胞毒性或促炎细胞因子分泌。随着白色念珠菌感染剂量增加，观察到紧密连接和黏附连接破坏导致屏障完整性降低，细胞毒性也增加。
我们的研究结果表明，白色念珠菌可利用跨细胞迁移侵入中枢神经系统，并能够规避主要的宿主免疫反应，这可能会影响诊断和预防策略。
