Rodriguez Matias E, Hassan Ali, Linaroudis Nikolaos, Harryson-Oliveberg Felix, Ten Hoeve Arne L, Barragan Antonio
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691, Stockholm, Sweden.
Nat Commun. 2025 Apr 14;16(1):3529. doi: 10.1038/s41467-025-58655-z.
Microbial translocation across the blood-brain barrier (BBB) is a prerequisite for colonization of the central nervous system. The obligate intracellular parasite Toxoplasma gondii chronically infects the brain parenchyma of humans and animals, in a remarkably stealthy fashion. We investigated the mechanisms of BBB traversal by T. gondii (genotypes I, II, III) and T. gondii-infected leukocytes, using intracarotid arterial delivery into the cerebral circulation of mice. Unexpectedly, parasitized dendritic cells (DCs) and other peripheral blood mononuclear cells were found to persistently sequester within cortical capillaries. Post-replicative egress of T. gondii from sequestered DCs was followed by rapid parasite localization within cortical neurons. Infection-induced microvascular inflammation dramatically elevated the sequestration of parasitized DCs, while treatments targeting the ICAM-1/CD18 leukocyte adhesion axis with blocking antibodies strongly reverted sequestration. The parasite effectors TgWIP and GRA15, known to promote leukocyte hypermigration and inflammatory activation, further increased both the capillary sequestration of infected DCs and cerebral parasite loads in a strain-dependent manner. These findings reveal that the sequestration of parasitized leukocytes in cortical capillaries, with subsequent BBB traversal following parasite egress, provides a mechanism for T. gondii's rapid access to cortical neurons during primary infection.
微生物穿过血脑屏障（BBB）是中枢神经系统定植的先决条件。专性细胞内寄生虫刚地弓形虫以一种非常隐秘的方式长期感染人类和动物的脑实质。我们利用向小鼠脑循环内颈动脉注射的方法，研究了刚地弓形虫（基因型I、II、III）和刚地弓形虫感染的白细胞穿越血脑屏障的机制。出乎意料的是，发现被寄生的树突状细胞（DCs）和其他外周血单核细胞持续隔离在皮质毛细血管内。刚地弓形虫从隔离的DCs中复制后逸出，随后迅速在皮质神经元中定位。感染诱导的微血管炎症显著增加了被寄生DCs的隔离，而用阻断抗体靶向ICAM-1/CD18白细胞粘附轴的治疗强烈逆转了隔离。已知促进白细胞过度迁移和炎症激活的寄生虫效应子TgWIP和GRA15，以菌株依赖的方式进一步增加了感染DCs的毛细血管隔离和脑内寄生虫负荷。这些发现表明，被寄生的白细胞在皮质毛细血管中的隔离，以及寄生虫逸出后随后的血脑屏障穿越，为刚地弓形虫在初次感染期间快速进入皮质神经元提供了一种机制。
