Intracellular cyclic AMP levels modulate differential adaptive responses on epimastigotes and cell culture trypomastigotes of Trypanosoma cruzi

Abstract

Among the many environmental challenges the parasite Trypanosoma cruzi has to overcome to complete its life cycle through different hosts, oxidative stress plays a central role.Different stages of this parasite encounter distinct sources of oxidative stress, such as the oxidative burst of the immune system, or the Heme released from hemoglobin degradation in the triatomine's midgut. Also, the redox status of the surroundings functions as a signal to the parasite, triggering processes coupled to differentiation or proliferation. Intracellular second messengers, like cAMP, are responsible for the transduction of environmental queues and initiating cellular processes accordingly. In trypanosomatids cAMP is involved in a variety of processes, including proliferation, differentiation, osmoregulation and quorum sensing. Trypanosomatid phosphodiesterases (PDE) show atypical pharmacological properties and some have been involved in key processes for the survival of the parasites, which validates them as attractive therapeutic targets. Our work here shows that cAMP modulates different processes according to parasite stage. Epimastigotes become more resistant to oxidative stress when pre-treated with cAMP analogs, while trypomastigotes do not alter their response to oxidative stress under the same treatment. However, cAMP analogs . CC-BY-NC-ND 4.

Efficacy of Novel Pyrazolone Phosphodiesterase Inhibitors in Experimental Mouse Models of Trypanosoma cruzi

“…PDEs structurally related to human isoforms have been reported in all trypanosomatids (PDEA, PDEB1/B2, PDEC, and PDED) (8). In Trypanosoma cruzi, the causative agent of CD, PDEC is localized into the contractile vacuole complex (CVC), which is essential for parasite fitness, and its inhibition causes dysregulation of the osmotic control, indicating the potential use of PDEs inhibitors as drug targets in this parasite (9,10). The fact that control of cyclic nucleotide metabolism is essential in kinetoplastid parasites, and the catalytic domains of their PDEs align closely with human homologues (10), justifies the potential repurposing of PDE inhibitor classes as potential antiparasitic agents (11), since such inhibitors have been successfully used for a large spectrum of clinical conditions, such as intermittent claudication, chronic obstructive pulmonary disease, erectile dysfunction (12), and psoriatic arthritis (13).…”