Kanatani Sachie, Fuks Jonas M, Olafsson Einar B, Westermark Linda, Chambers Benedict, Varas-Godoy Manuel, Uhlén Per, Barragan Antonio
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
PLoS Pathog. 2017 Dec 7;13(12):e1006739. doi: 10.1371/journal.ppat.1006739. eCollection 2017 Dec.
The obligate intracellular parasite Toxoplasma gondii exploits cells of the immune system to disseminate. Upon T. gondii-infection, γ-aminobutyric acid (GABA)/GABAA receptor signaling triggers a hypermigratory phenotype in dendritic cells (DCs) by unknown signal transduction pathways. Here, we demonstrate that calcium (Ca2+) signaling in DCs is indispensable for T. gondii-induced DC hypermotility and transmigration in vitro. We report that activation of GABAA receptors by GABA induces transient Ca2+ entry in DCs. Murine bone marrow-derived DCs preferentially expressed the L-type voltage-dependent Ca2+ channel (VDCC) subtype Cav1.3. Silencing of Cav1.3 by short hairpin RNA or selective pharmacological antagonism of VDCCs abolished the Toxoplasma-induced hypermigratory phenotype. In a mouse model of toxoplasmosis, VDCC inhibition of adoptively transferred Toxoplasma-infected DCs delayed the appearance of cell-associated parasites in the blood circulation and reduced parasite dissemination to target organs. The present data establish that T. gondii-induced hypermigration of DCs requires signaling via VDCCs and that Ca2+ acts as a second messenger to GABAergic signaling via the VDCC Cav1.3. The findings define a novel motility-related signaling axis in DCs and unveil that interneurons and DCs share common GABAergic motogenic pathways. T. gondii employs GABAergic non-canonical pathways to induce host cell migration and facilitate dissemination.
专性细胞内寄生虫刚地弓形虫利用免疫系统的细胞进行传播。在刚地弓形虫感染后，γ-氨基丁酸（GABA）/GABAA受体信号通过未知的信号转导途径触发树突状细胞（DCs）的高迁移表型。在此，我们证明DCs中的钙（Ca2+）信号对于刚地弓形虫诱导的DCs体外高迁移率和迁移是不可或缺的。我们报道GABA对GABAA受体的激活诱导DCs中短暂的Ca2+内流。小鼠骨髓来源的DCs优先表达L型电压依赖性Ca2+通道（VDCC）亚型Cav1.3。通过短发夹RNA沉默Cav1.3或对VDCCs进行选择性药理学拮抗消除了弓形虫诱导的高迁移表型。在弓形虫病小鼠模型中，对过继转移的弓形虫感染的DCs进行VDCC抑制延迟了血液循环中细胞相关寄生虫的出现，并减少了寄生虫向靶器官的传播。目前的数据表明，刚地弓形虫诱导的DCs高迁移需要通过VDCCs进行信号传导，并且Ca2+作为通过VDCC Cav1.3的GABA能信号的第二信使。这些发现定义了DCs中一个新的与迁移相关的信号轴，并揭示了中间神经元和DCs共享共同的GABA能促迁移途径。刚地弓形虫利用GABA能非经典途径诱导宿主细胞迁移并促进传播。
