Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi

Abstract

There is no effective cure for Chagas disease, which is caused by infection with the arthropod-borne parasite, Trypanosoma cruzi. In the search for new drugs to treat Chagas disease, potential therapeutic targets have been identified by exploiting the differences between the mechanisms involved in intracellular Ca 2+ homeostasis, both in humans and in trypanosomatids. In the trypanosomatid, intracellular Ca 2+ regulation requires the concerted action of three intracellular organelles, the endoplasmic reticulum, the single unique mitochondrion, and the acidocalcisomes. The single unique mitochondrion and the acidocalcisomes also play central roles in parasite bioenergetics. At the parasite plasma membrane, a Ca 2+-− ATPase (PMCA) with significant differences from its human counterpart is responsible for Ca 2+ extrusion; a distinctive sphingosine-activated Ca 2+ channel controls Ca 2+ entrance to the parasite interior. Several potential anti-trypansosomatid drugs have been demonstrated to modulate one or more of these mechanisms for Ca 2+ regulation. The antiarrhythmic agent amiodarone and its derivatives have been shown to exert trypanocidal effects through the disruption of parasite Ca 2+ homeostasis. Similarly, the amiodarone-derivative dronedarone disrupts Ca 2+ homeostasis in T. cruzi epimastigotes, collapsing the mitochondrial membrane potential (Ψ m), and inducing a large increase in the intracellular Ca 2+ concentration ([Ca 2+ ] i) from this organelle and from the acidocalcisomes in the parasite cytoplasm. The same general mechanism has been demonstrated for SQ109, a new anti-tuberculosis drug with potent trypanocidal effect. Miltefosine similarly induces a large increase in the [Ca 2+ ] i acting on the sphingosine-activated Ca 2+ channel, the mitochondrion and acidocalcisomes. These examples, in conjunction with other evidence we review herein, strongly support targeting Ca 2+ homeostasis as a strategy against Chagas disease.

Trypanosoma cruzi Modulates PIWI-Interacting RNA Expression in Primary Human Cardiac Myocytes during the Early Phase of Infection

“…Others showed that active TGF-β is very important during T. cruzi infection [ 21 ]. T. cruzi has been reported to dysregulate calcium homeostasis to facilitate cellular infection [ 22 ]. Calcium binds to calmodulin (CaM) and activates the phosphatase calcineurin and CaM Kinase II [ 23 ].…”

Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs

“…The combine of both actions will lead to a large parasite-specific intracellular accumulation of Ca +2 [69]. Since disruption of the intracellular Ca +2 homeostasis has been described as an important drug target in trypanosomatids [40,42,71], miltefosine could indeed be an interesting drug candidate to pursue for Chagas disease. In fact, several studies have reported in vitro susceptibility of T. cruzi parasites to miltefosine [40][41][42].…”

Ethanolic Extract of the Fungus Trichoderma asperelloides Induces Ultrastructural Effects and Death on Leishmania amazonensis

“…In this regard, trypanocidal compounds such as squalene synthase inhibitors may also cause contractile vacuole enlargement (Braga et al, 2004 ). It remains to be determined whether the osmoregulatory mechanism could be involved in cell death mechanism triggered by fungal derivatives, but calcium homeostasis is involved in the mode of action of antiparasitic agents on Leishmania donovani (Pinto-Martinez et al, 2018 ) and Trypanosoma cruzi (Benaim et al, 2020 ). Lipid body formation may comprise an escape mechanism as this compartment is an intracellular site of synthesis of prostaglandins, such as PGF 2a , inhibiting different facets of the immune response (Vallochi et al, 2018 ).…”