Ancient Plant Pathway Controls Calcium Signaling in Toxoplasma gondii

Parasitology researchers have found that using drugs that inhibit an ancient plant-related metabolic pathway might be the most efficient way of attacking Toxoplasma gondii, one of the most common human parasites.

This protozoan parasite causes toxoplasmosis, which in about 60% of healthy adults causes no symptoms. Most of the remaining 40% experience mild, flu-like symptoms, low-grade fever, and fatigue that resolve without intervention in a few weeks. Once exposed, reinfection does not occur in healthy individuals. However, in immunocompromised individuals, such as those with HIV/AIDS, symptoms can be severe, life threatening, and recurring. T. gondii infection of a fetus or newborn can also cause severe neurologic impairment, blindness, mental retardation, and death.

Investigators from the Washington University School of Medicine (St. Louis, MO, USA) were seeking the parasite's mechanism for controlling calcium signaling. This is very important, as calcium manages a number of critical events, including motility, secretion, cell invasion, and egress by the parasites.

Earlier results had shown that plant-like metabolic pathways could be involved, therefore the investigators looked at the effects of the plant hormone abscisic acid (ABA). In plants, ABA controls a number of important events, including environmental stress responses, embryo development, and seed dormancy. ABA induces production of the second-messenger cyclic ADP ribose (cADPR), which controls release of intracellular calcium stores in plants. cADPR also controls intracellular calcium release in the T. gondii. The investigators speculated that the pathway for ABA production was probably acquired from an algal endosymbiont that was retained as a non-photosynthetic plastid known as the apicoplast.

Production of endogenous ABA within the parasite was confirmed by purification (using high-performance liquid chromatography) and analysis (by gas chromatography-mass spectrometry). Furthermore, results published in the January 10, 2008, issue of the journal Nature revealed that selective disruption of ABA synthesis by the inhibitor fluridone delayed egress and induced development of the slow growing, dormant cyst stage of the parasite. The investigators suggested that the plant-like nature of this pathway could be exploited therapeutically, since a specific inhibitor of ABA synthesis was able to prevent toxoplasmosis in the mouse model.

"As a target for drug development, this pathway is very attractive for several reasons,” said senior author Dr, L. David Sibley, professor of molecular microbiology at the Washington University School of Medicine. "For example, because of its many roles in plant biology, we already have several inhibitors for it. Also, the plant-like nature of the target decreases the chances that blocking it with a drug will have significant negative side effects in human patients. Signals are sometimes even better targets for drug development than biosynthetic pathways. Taking out a biosynthetic pathway means you take away one thing from the parasite. But if you can successfully disable a key signal, this may potentially disrupt many more aspects of the parasite's metabolism.”


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