Dual and Opposite Roles of Reactive Oxygen Species (ROS) in Chagas Disease: Beneficial on the Pathogen and Harmful on the Host

Abstract

Chagas disease is a neglected tropical disease, which affects an estimate of 6-7 million people worldwide. Chagas disease is caused by Trypanosoma cruzi, which is a eukaryotic flagellate unicellular organism. At the primary infection sites, these parasites are phagocytized by macrophages, which produce reactive oxygen species (ROS) in response to the infection with T. cruzi. The ROS produce damage to the host tissues; however, macrophage-produced ROS is also used as a signal for T. cruzi proliferation. At the later stages of infection, mitochondrial ROS is produced by the infected cardiomyocytes that contribute to the oxidative damage, which persists at the chronic stage of the disease. The oxidative damage leads to a functional impairment of the heart. In this review article, we will discuss the mechanisms by which T. cruzi is able to deal with the oxidative stress and how this helps the parasite growth at the acute phase of infection and how the oxidative stress affects the cardiomyopathy at the chronic stage of the Chagas disease. We will describe the mechanisms used by the parasite to deal with ROS and reactive nitrogen species (RNS) through the trypanothione and the mechanisms used to repair the damaged DNA. Also, a description of the events produced by ROS at the acute and chronic stages of the disease is presented. Lastly, we discuss the benefits of ROS for T. cruzi growth and proliferation and the possible mechanisms involved in this phenomenon. Hypothesis is put forward to explain the molecular mechanisms by which ROS triggers parasite growth and proliferation and how ROS is able to produce a long persisting damage on cardiomyocytes even in the absence of the parasite.

(-)-T-Cadinol—a Sesquiterpene Isolated From Casearia sylvestris (Salicaceae)—Displayed In Vitro Activity and Causes Hyperpolarization of the Membrane Potential of Trypanosoma cruzi

“…Under normal conditions, the respiratory chain generates around 3–5% of ROS over the total oxygen consumed, and these species are used as signalization in the cell proliferation and growth. Therefore, derangements in the mitochondria can affect the production of these species, caused from interference in different biosynthetic pathways to lethal oxidative stress (Machado-Silva et al, 2016 ; Maldonado et al, 2020 ). Considering the effect of compound 1 in the mitochondria, the ROS levels in T. cruzi using the fluorescent probe H 2 DCFDA was also investigated.…”

Oxidative Stress as a Therapeutic Target in Amyotrophic Lateral Sclerosis: Opportunities and Limitations

“…These include hydrogen peroxide (H 2 O 2 ), nitric oxide (NO), superoxide (O 2 •− ), peroxide (O 2 •−2 ), hydroxyl ion (OH − ), and reactive hydroxyl radicals ( • OH), which are generated by multiple cellular processes [ 14 ]. ROS play important roles in both physiological and pathological conditions, because they can induce opposing effects on cellular metabolism and can act as beneficial or harmful molecules [ 15 ].…”

In Search of the Vaccine Against Chagas Disease: A Tedious Road of More Than 100 Years

“…On the other hand, in most cases, the specific immune response generated against T. cruzi does not eliminate the parasite efficiently and its persistence is generated in the host, this being a factor for the appearance of the pathology in the chronic phase, this is why the elimination of the parasite in the acute phase would be of importance in preventing the survival of the parasite and preventing the development of chagasic pathologies. In this sense, prophylactic vaccination would be more appropriate [25].…”

“…It should be noted that a limitation in a large part of the vaccine candidates evaluated is that they have been mainly tested in murine models, so it is unknown whether this observed efficacy is similar in humans. This leads to the use of other animal models, such as dogs [115], non-human primates [25], as well as the cellular response in chagasic patients [20], and mixed therapy trials have been carried out where low-dose chemotherapeutic treatment is combined with the application of vaccines [4], which in some cases it reduces heart disease [21] in others oxidative damage is controlled, observing a cardioprotective effect [116][117][118].…”

“…Multiple vaccine prototypes have been tested and have shown to be good candidates in terms of protection and with great advantages for their production and application [19][20][21][22][23][24]. During infection, the immune response that is generated against the parasite is not enough to neutralize and/ or eliminate it, this being the main factor in the persistence of the parasite as well as the development of the chronic phase of the disease; where the parasite load and the unbalance of oxidative stress generate the damage in the host tissue [25], therefore, the control of T. cruzi by activating the immune system during the acute phase of the disease would prevent the development of the pathology [26]. This work aims to highlight the efforts, progress and show the different approaches in the development of the vaccine against ChD.…”