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

Abstract

Cyclic adenosine diphosphoribose (cADPR) is an endogenous Ca 2+ -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 Ca 2+ 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 Ca 2+ 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.