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

Amol K Bhandage,Elizabeth Thompson,Karin Loré,Gabriela C Olivera,Antonio Barragan,Manuel Varas-Godoy,Sachie Kanatani

doi:10.7554/elife.60528

Amol K Bhandage, Elizabeth Thompson + Show 5 more

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https://doi.org/10.7554/elife.60528

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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.

Highlights

Gamma-aminobutyric acid (GABA), first identified as a plant and microbe metabolite, is a principal neurotransmitter in the central nervous system (CNS) of vertebrates (Roth et al, 2003)
We identified and performed functional tests on the five principal components of GABAergic signaling, namely (i) GABA metabolism, (ii) GABA transportation and secretion, (iii) GABA-A R activation, (iv) GABA signaling regulators cation-chloride cotransporters (CCCs) and (v) effector Ca2+ channel signaling by voltage-dependent calcium (Ca2+) channels (VDCCs) (Figure 10)
We demonstrate that a conserved expression of GABAergic molecular components is functionally linked to motility and migratory activation of mononuclear phagocytes upon infection challenge

Summary

Introduction

Gamma-aminobutyric acid (GABA), first identified as a plant and microbe metabolite, is a principal neurotransmitter in the central nervous system (CNS) of vertebrates (Roth et al, 2003). Neurons and other GABAergic cells synthesize GABA via glutamate decarboxylases (GAD65/67) (Soghomonian and Martin, 1998). The GABA-A Rs are pentameric ionotropic chloride channels, normally comprised of three types of subunits: 2 as, 2 bs and a third type of subunit. Nineteen different mammalian GABA-A R subunits (a1–6, b1–3, g1–3, d, e, p, q and r1–3) can combine to form numerous variants of functional heteromeric receptors in neuronal cells. The strength and polarity of GABA signaling is regulated by cation-chloride cotransporters (CCCs) (Kaila et al, 2014). GABA-A R activation by GABA can elicit opening of voltage-dependent calcium (Ca2+) channels (VDCCs) with subsequent Ca2+ influx into the neuronal cell (Bortone and Polleux, 2009)

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