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

Abstract

Heme is a ubiquitous molecule that has a number of physiological roles. The toxic effects of this molecule have been demonstrated in various models, based on both its pro-oxidant nature and through a detergent mechanism. It is estimated that about 10 mM of heme is released during blood digestion in the blood-sucking bug's midgut. The parasite Trypanosoma cruzi, the agent of Chagas' disease, proliferates in the midgut of the insect vector; however, heme metabolism in trypanosomatids remains to be elucidated. Here we provide a mechanistic explanation for the proliferative effects of heme on trypanosomatids. Heme, but not other porphyrins, induced T. cruzi proliferation, and this phenomenon was accompanied by a marked increase in reactive oxygen species (ROS) formation in epimastigotes when monitored by ROS-sensitive fluorescent probes. Heme-induced ROS production was time-and concentration-dependent. In addition, lipid peroxidation and the formation of 4-hydroxy-2-nonenal (4-HNE) adducts with parasite proteins were increased in epimastigotes in the presence of heme. Conversely, the antioxidants urate and GSH reversed the heme-induced ROS. Urate also decreased parasite proliferation. Among several protein kinase inhibitors tested only specific inhibitors of CaMKII, KN93 and Myr-AIP, were able to abolish heme-induced ROS formation in epimastigotes leading to parasite growth impairment. Taken together, these data provide new insight into T. cruzi- insect vector interactions: heme, a molecule from the blood digestion, triggers epimastigote proliferation through a redox-sensitive signalling mechanism.

Oxidative Stress and DNA Lesions: The Role of 8-Oxoguanine Lesions in Trypanosoma cruzi Cell Viability

“…In summary, we demonstrated that modifying the expression levels of an element from the 8-oxoG repair system can influence the parasite cell viability in both replicative phases, as previously observed for the parasite antioxidant machinery [62]. Considering that oxidative stress is important to T. cruzi proliferation in both replicative forms as demonstrated by Paiva et al [54] and Nogueira et al [53], mechanism for counteracting DNA oxidative damage would be of great importance for this parasite. T. cruzi DNA repair machinery presents some particular features from typical eukaryotic DNA repair machinery.…”

“…The recent findings of Nogueira et al [53] confirm that low levels of ROS production induced by heme in T. cruzi epimastigotes favors parasite proliferation via a Ca 2+ calmodulin kinase II (CaMKII)-like pathway. In addition, antioxidant activity (urate and GSH) inhibited heme-induced ROS and parasite proliferation [53]. In addition, Paiva et al [54] demonstrated that maintenance of high parasite burden during T. cruzi infection might be dependent of oxidative stress generation.…”

“…Apparently, pre-treatment induces an increase in TcCPX levels from the parasite antioxidant network, preparing the parasite to address the fluctuating levels of ROS [23]. The recent findings of Nogueira et al [53] confirm that low levels of ROS production induced by heme in T. cruzi epimastigotes favors parasite proliferation via a Ca 2+ calmodulin kinase II (CaMKII)-like pathway. In addition, antioxidant activity (urate and GSH) inhibited heme-induced ROS and parasite proliferation [53].…”

Modulation of mitochondrial metabolism as a biochemical trait in blood feeding organisms: the redox vampire hypothesis redux

“…However, the consequences to redox homeostasis revealed to be more complex than previously anticipated. While insect vectors reduce mitochondrial oxidant production in different species and tissues (Gonçalves et al, ; Oliveira et al, ; Bottino‐Rojas et al, ; Gandara et al, ), blood dwelling parasites boost mitochondrial ROS generation when exposed to blood products (Gonçalves et al, ; Nogueira et al, ; Oliveira et al, ; Nogueira et al, ). Despite important biological aspects underlying the management of a blood meal, including diuresis, host hormone signaling, and nutritional overload were previously reviewed (Luckhart and Riehle, ; Orchard, ; Sterkel et al, ), here, we will discuss how blood derived products modulates energy metabolism in hematophagous organisms of medical importance, focusing on the observed changes in mitochondrial function and structure.…”

Calcium signaling in trypanosomatid parasites

“…Heme-induced proliferation of T. cruzi culture forms is mediated by activation of a CaMKII and prevented by inhibitors of this enzyme (KN-93, Myr-AIP) [74]. Activation of this CaMKII is mediated by the enhanced reactive oxygen species (ROS) formation by heme [75,76]. …”