Back from the Dormant Stage: Second Messenger Cyclic ADP-Ribose Essential for Toxoplasma gondii Pathogenicity

Andreas H. Guse^*

The Calcium Signalling Group, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Centre of Experimental Medicine, University Medical Centre Hamburg–Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.

Abstract: Cyclic adenosine diphosphoribose (cADPR) is an endogenous Ca²⁺-mobilizing second messenger found in cells of animals, plants, and protozoans. It is formed by a specific class of enzymes, the ADP-ribosyl cyclases. cADPR stimulates Ca²⁺ release by means of ryanodine receptors located in the sarcoplasmic and endoplasmic reticulum. Recently, a role for cADPR has been demonstrated in the obligate intracellular protozoan pathogen Toxoplasma gondii. In T. gondii, stress conditions evoked synthesis of the plant hormone abscisic acid by the apicoplast, a remnant organelle of an algal endosymbiont of T. gondii. Abscisic acid in turn activated formation of cADPR within T. gondii, resulting in Ca²⁺ release and secretion of proteins involved in egress of T. gondii from its host cell. Evidence for a synthetic pathway of plant origin was obtained with the ABA synthesis inhibitor fluridone, which antagonized cellular egress and induced differentiation of long-lived semidormant cystic forms of T. gondii. Moreover, fluridone protected mice from toxoplasmosis.

*Corresponding author. E-mail, guse{at}uke.uni-hamburg.de

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