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.
Highlights
Chagas disease or American trypanosomiasis is an endemic zoonosis in South and Central America characterized by chronic inflammation and cardiomyopathy, and less frequently, digestive symptoms
Prostaglandin F2α (PGF2α), thromboxane A2 (TXA2), prostaglandin I2 (PGI2), and prostaglandin E2 (PGE2) levels were shown to increase in infected mice [8, 9], and T. cruzi-derived eicosanoids were proposed as a mechanism of parasite persistence [10] as they are involved in disease evolution in favor of progression to the chronic stage [11, 12]
To examine how TcOYE is related to other proteins sharing sequence similarity, we performed a phylogenetic analysis (Figure 1) using proteins annotated as Old Yellow Enzymes in the KEGG Orthology database and manually recovered from published studies
Summary
Chagas disease or American trypanosomiasis is an endemic zoonosis in South and Central America characterized by chronic inflammation and cardiomyopathy, and less frequently, digestive symptoms. Prostaglandin F2α (PGF2α), thromboxane A2 (TXA2), prostaglandin I2 (PGI2), and prostaglandin E2 (PGE2) levels were shown to increase in infected mice [8, 9], and T. cruzi-derived eicosanoids were proposed as a mechanism of parasite persistence [10] as they are involved in disease evolution in favor of progression to the chronic stage [11, 12]. In this sense, it was proposed that transition to the chronic phase is affected by the immunomodulatory effect of eicosanoids released by T. cruzi, which may contribute to parasite proliferation and differentiation, and to host survival [11, 12]. TXA2 and PGF2α were found to be the most abundant bioactive eicosanoids derived from T. cruzi during infection [11]
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