A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites

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Abstract

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.

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All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

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Amol K Bhandage

Molecular Biosciences, Stockholm University, Stockholm, Sweden

For correspondence
amol.bhandage@su.se

Competing interests
The authors declare that no competing interests exist.
Gabriella C Olivera

Molecular Biosciences, Stockholm University, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.
Sachie Kanatani

Molecular Biosciences, Stockholm University, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.
Elizabeth Thompson

Medicine, Solna, Karolinska Institutet, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.
Karin Loré

Medicine Solna, Karolinska Institutet, Stockholm, Sweden

Competing interests
The authors declare that no competing interests exist.
Manuel Varas-Godoy

Faculty of Medicine and Science, Universidad San Sebastian, Santiago de Chile, Chile

Competing interests
The authors declare that no competing interests exist.
Antonio Barragan

Molecular Biosciences, Stockholm University, Stockholm, Sweden

For correspondence
antonio.barragan@su.se

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7746-9964

Funding

Vetenskapsrådet (2018-02411)

Antonio Barragan

Olle Engkvist Foundation (193-609)

Amol K Bhandage

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

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.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.