Abscisic acid controls calcium-dependent egress and development in Toxoplasma gondii

Abstract

Calcium signalling plays an important role in determining the virulence of the human pathogen Toxoplasma gondii, an apicomplexan protozoon. A study of the mechanisms involved has uncovered a surprising agent for this signalling: the plant hormone abscisic acid. Comparative genomics reveals that the pathway for synthesis of the plant hormone was acquired by endosymbiosis. This pathway controls a crucial developmental switch between lytic growth and dormancy, which is a key component of pathogenesis. The plant-like nature of this pathway may be exploited to develop new therapeutics as shown by the ability of a specific inhibitor of abscisic acid biosynthesis to protect mice from lethal infection. Calcium signalling is important for apicomplexan parasite virulence. A newly discovered calcium signalling pathway based on the plant hormone abscisic acid is now reported in Toxoplasma gondii. As this pathway is absent in most animals, it may present a new target for drug intervention. 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 dormancy4,5. 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. gondii7,8; 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.