Voltage-dependent calcium channel signaling mediates GABAA receptor-induced migratory activation of dendritic cells infected by Toxoplasma gondii

PLoS Pathogens

Benedict Chambers¹  Per Uhlén²  Linda Westermark³  Jonas M. Fuks³  Einar B. Olafsson³  Sachie Kanatani³  Manuel Varas-Godoy⁴  Antonio Barragan⁴ 

[1] Center for Infectious Medicine, Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden;Centro de Investigacion Biomedica, Faculty of Medicine, Universidad de los Andes, Santiago, Chile;Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden;Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, Sweden

关键词: Parasitic diseases;    Toxoplasma gondii;    Tachyzoites;    Gamma-aminobutyric acid;    Spleen;    Jaw;    Blood;    Cell membranes;   

DOI  :  10.1371/journal.ppat.1006739

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY