Heme-induced Trypanosoma cruzi proliferation is mediated by CaM kinase II

Abstract

Trypanosoma cruzi, the etiologic agent of Chagas disease, is transmitted through triatomine vectors during their blood-meal on vertebrate hosts. These hematophagous insects usually ingest approximately 10mM of heme bound to hemoglobin in a single meal. Blood forms of the parasite are transformed into epimastigotes in the crop which initiates a few hours after parasite ingestion. In a previous work, we investigated the role of heme in parasite cell proliferation and showed that the addition of heme significantly increased parasite proliferation in a dose-dependent manner [1]. To investigate whether the heme effect is mediated by protein kinase signalling pathways, parasite proliferation was evaluated in the presence of several protein kinase (PK) inhibitors. We found that only KN-93, a classical inhibitor of calcium-calmodulin-dependent kinases (CaMKs), blocked heme-induced cell proliferation. KN-92, an inactive analogue of KN-93, was not able to block this effect. A T. cruzi CaMKII homologue is most likely the main enzyme involved in this process since parasite proliferation was also blocked when Myr-AIP, an inhibitory peptide for mammalian CaMKII, was included in the cell proliferation assay. Moreover, CaMK activity increased in parasite cells with the addition of heme as shown by immunological and biochemical assays. In conclusion, the present results are the first strong indications that CaMKII is involved in the heme-induced cell signalling pathway that mediates parasite proliferation.

The Role of Heme and Reactive Oxygen Species in Proliferation and Survival ofTrypanosoma cruzi

“…Moreover addition of KN 93 and Myr-AIP (inhibitors of calmodulin kinase) to a culture of these cells reduces the expected growth, indicating the involvement of calmodulin kinase in heme-mediated cell signaling [32]. Furthermore, the authors showed that heme-induced T. cruzi growth is associated with CaMKII [31], demonstrating a signaling role for the heme molecule in the biological cycle of Trypanosoma cruzi .…”

Heme-Induced ROS in Trypanosoma Cruzi Activates CaMKII-Like That Triggers Epimastigote Proliferation. One Helpful Effect of ROS

“…We have recently shown that heme-induced T. cruzi growth is associated with calcium-calmodulin-dependent kinase II (CaMKII) activity [31]. Based on previous evidence showing that heme can exert potent pro-oxidant actions [8], [11] and that CaMKII activity can be stimulated by oxidation [28], [29], here we hypothesized whether heme would drive T. cruzi proliferation through a redox dependent CaM Kinase II-like cascade and in fact, the data presented herein indicate that heme induces a transient oxidative stress condition that stimulates T. cruzi growth via a mechanism mediated by a CaM Kinase II-like pathway.…”

Physiological and unappreciated roles of CaMKII in the heart

“…Of note, CaMKII signaling was discovered to be involved in the progression of Chagas’ disease by enabling heme-induced cell proliferation of the Trypanosoma cruzi epimastigotes [67, 94]. Chagas disease is a potentially deadly disease afflicting many Latin American regions and its incidence is currently rising due to increased population mobility and non-vectorial transmission [76, 83].…”