1. Department of Molecular Microbiology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, Missouri 63110, USA
2. Donald Danforth Plant Science Center, 975 N. Warson Road, St Louis, Missouri 63132, USA
3. Department of Anesthesiology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA
4. Present addresses: Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan (K.N.); Linstitut National de la Researche Agronomique, Centre de Recherche de Tours, 37380 Nouzilly, France (F.B.).

Correspondence to: L. David Sibley¹ Correspondence and requests for materials should be addressed to L.D.S. (Email: sibley@wustl.edu).

Abstract

Calcium controls a number of critical events, including motility, secretion, cell invasion and egress by apicomplexan parasites¹. Compared to animal² and plant cells³, the molecular mechanisms that govern calcium signalling in parasites are poorly understood. Here we show that the production of the phytohormone abscisic acid (ABA) controls calcium signalling within the apicomplexan parasite Toxoplasma gondii, an opportunistic human pathogen. In plants, ABA controls a number of important events, including environmental stress responses, embryo development and seed dormancy^{4, 5}. ABA induces production of the second-messenger cyclic ADP ribose (cADPR), which controls release of intracellular calcium stores in plants⁶. cADPR also controls intracellular calcium release in the protozoan parasite T. gondii^{7, 8}; however, previous studies have not revealed the molecular basis of this pathway⁹. We found that addition of exogenous ABA induced formation of cADPR in T. gondii, stimulated calcium-dependent protein secretion, and induced parasite egress from the infected host cell in a density-dependent manner. Production of endogenous ABA within the parasite was confirmed by purification (using high-performance liquid chromatography) and analysis (by gas chromatography-mass spectrometry). Selective disruption of ABA synthesis by the inhibitor fluridone delayed egress and induced development of the slow-growing, dormant cyst stage of the parasite. Thus, ABA-mediated calcium signalling controls the decision between lytic and chronic stage growth, a developmental switch that is central in pathogenesis and transmission. The pathway for ABA production was probably acquired with an algal endosymbiont that was retained as a non-photosynthetic plastid known as the apicoplast. The plant-like nature of this pathway may be exploited therapeutically, as shown by the ability of a specific inhibitor of ABA synthesis to prevent toxoplasmosis in the mouse model.

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