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

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 <i>Toxoplasma gondii</i> and <i>Neospora caninum</i> activated GABAergic signaling in phagocytes. Using gene silencing and pharmacological modulators <i>in vitro</i> and <i>in vivo</i> 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 <i>Trojan horse</i> mechanism.