Old Yellow Enzyme from Trypanosoma cruzi Exhibits In Vivo Prostaglandin F2α Synthase Activity and Has a Key Role in Parasite Infection and Drug Susceptibility

Abstract

The discovery that trypanosomatids, unicellular organisms of the order Kinetoplastida, are capable of synthesizing prostaglandins raised questions about the role of these molecules during parasitic infections. Multiple studies indicate that prostaglandins could be related to the infection processes and pathogenesis in trypanosomatids. This work aimed to unveil the role of the prostaglandin F2α synthase TcOYE in the establishment of Trypanosoma cruzi infection, the causative agent of Chagas disease. This chronic disease affects several million people in Latin America causing high morbidity and mortality. Here, we propose a prokaryotic evolutionary origin for TcOYE, and then we used in vitro and in vivo experiments to show that T. cruzi prostaglandin F2α synthase plays an important role in modulating the infection process. TcOYE overexpressing parasites were less able to complete the infective cycle in cell culture infections and increased cardiac tissue parasitic load in infected mice. Additionally, parasites overexpressing the enzyme increased PGF2α synthesis from arachidonic acid. Finally, an increase in benznidazole and nifurtimox susceptibility in TcOYE overexpressing parasites showed its participation in activating the currently anti-chagasic drugs, which added to its observed ability to confer resistance to hydrogen peroxide, highlights the relevance of this enzyme in multiple events including host–parasite interaction.

The fecal, oral, and skin microbiota of children with Chagas disease treated with benznidazole

“…By the contrary, Bnz needs to be activated and in T . cruzi the nitroreductases NTR I and Tc OYE are the main responsible for this activation [28–29]. Interestingly, both nitroreductases belong to highly conserved families in prokaryotes, and even a bacterial origin through horizontal transfer has been postulated for Tc OYE [29].…”

“…cruzi the nitroreductases NTR I and Tc OYE are the main responsible for this activation [28–29]. Interestingly, both nitroreductases belong to highly conserved families in prokaryotes, and even a bacterial origin through horizontal transfer has been postulated for Tc OYE [29]. We therefore postulate that activation of Bnz could account immediately after ingestion by bacterial nitroreductases, although it deserves to be studied in detail.…”

Defeating the trypanosomatid trio: proteomics of the protozoan parasites causing neglected tropical diseases

“…A total of six proteins namely protein transport protein Sec23A, YXKO-related protein, α-tubulin, β-tubulin, β-tubulin 1.9 and T. cruzi aldo-keto reductase (TcAKR) were identified. As TcAKR is related to enzymes previously reported to be associated with Bzn reductive activation, such as T. cruzi nitroreductase (TcNTRI) 136 and T. cruzi prostaglandin F2α synthase/old yellow enzyme (TcOYE), 137 the study points to the possibility of reductive activation pathways for the drug action. However, the lack of competitive binding controls in this study makes arriving at definitive conclusions regarding the mechanism of action difficult.…”

Co‐opting oxylipin signals in microbial disease

“…These findings suggest that T. cruzi exploits the TXA 2 ‐thromboxane receptor signalling to prevent host from early death and maintain infection longevity. PGF 2 synthase TcOYE is important for completion and progression of its infective cycle (Díaz‐Viraqué et al, ). The TcOYE overexpression mutant displays more aggressive parasitemia and increased parasitic load in cardiac tissue.…”