Gamma-aminobutyric acid (GABA) serves diverse biological functions in prokaryotes and eukaryotes, including neurotransmission in vertebrates. Yet, the role of GABA in the immune system has remained elusive. Here, a comprehensive characterization of human and murine myeloid mononuclear phagocytes revealed the presence of a conserved and tightly regulated GABAergic machinery with expression of GABA metabolic enzymes and transporters, GABA-A receptors and regulators, and voltage-dependent calcium channels. Infection challenge with the common coccidian parasites Toxoplasma gondii and Neospora caninum activated GABAergic signaling in phagocytes. Using gene silencing and pharmacological modulators in vitro and in vivo in mice, we identify the functional determinants of GABAergic signaling in parasitized phagocytes and demonstrate a link to calcium responses and migratory activation. The findings reveal a regulatory role for a GABAergic signaling machinery in the host-pathogen interplay between phagocytes and invasive coccidian parasites. The co-option of GABA underlies colonization of the host by a Trojan horse mechanism.
- Antonio Barragan
- Amol K Bhandage
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All the animal experimentation procedures involving infection and extraction of cells/organs from mice were approved by Regional Animal Research Ethical Board, Stockholm, Sweden in concordance with in EU legislation (permit numbers 9707/2018, 14458/2019 and N 78/16).
Human subjects: The Regional Ethics Committee, Stockholm, Sweden, approved protocols involving human cells. All donors received written and oral information upon donation of blood at the Karolinska University Hospital.
- Xiaoyu Hu, Tsinghua University, China
© 2020, Bhandage et al.
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