GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii

PLoS Pathogens

Jessica M. Weidner¹  Zhe Jin¹  Jonas M. Fuks¹  Antonio Barragan¹  Bence Rethi²  Bryndis Birnir²  Robert P. A. Wallin³  Suresh Kumar Mendu³  Romanico B. G. Arrighi³ 

[1] Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden;Department of Neuroscience, Uppsala University, Uppsala, Sweden;Swedish Institute for Communicable Disease Control, Stockholm, Sweden

关键词: Parasitic diseases;    Toxoplasma gondii;    Gamma-aminobutyric acid;    Tachyzoites;    Secretion;    Monocytes;    Chemokines;    Chemotaxis;   

DOI  :  10.1371/journal.ppat.1003051

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

During acute infection in human and animal hosts, the obligate intracellular protozoan Toxoplasma gondii infects a variety of cell types, including leukocytes. Poised to respond to invading pathogens, dendritic cells (DC) may also be exploited by T. gondii for spread in the infected host. Here, we report that human and mouse myeloid DC possess functional γ-aminobutyric acid (GABA) receptors and the machinery for GABA biosynthesis and secretion. Shortly after T. gondii infection (genotypes I, II and III), DC responded with enhanced GABA secretion in vitro. We demonstrate that GABA activates GABAA receptor-mediated currents in T. gondii-infected DC, which exhibit a hypermigratory phenotype. Inhibition of GABA synthesis, transportation or GABAA receptor blockade in T. gondii-infected DC resulted in impaired transmigration capacity, motility and chemotactic response to CCL19 in vitro. Moreover, exogenous GABA or supernatant from infected DC restored the migration of infected DC in vitro. In a mouse model of toxoplasmosis, adoptive transfer of infected DC pre-treated with GABAergic inhibitors reduced parasite dissemination and parasite loads in target organs, e.g. the central nervous system. Altogether, we provide evidence that GABAergic signaling modulates the migratory properties of DC and that T. gondii likely makes use of this pathway for dissemination. The findings unveil that GABA, the principal inhibitory neurotransmitter in the brain, has activation functions in the immune system that may be hijacked by intracellular pathogens.

【 授权许可】

CC BY