Trypanosoma cruzi Needs a Signal Provided by Reactive Oxygen Species to Infect Macrophages

Goes, Grazielle Ribeiro; Rocha, Peter; Diniz, Aline R. S.; Aguiar, Pedro Henrique Nascimento; Machado, Carlos Renato; Vieira, Leda Quércia

doi:10.1371/journal.pntd.0004555

Cited by 63 publications

(82 citation statements)

References 81 publications

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“…Our in vitro experiments demonstrated that deficiency of AhR did not change NO levels but resulted in a decrease in ROS production upon T. cruzi infection. Since killing of T. cruzi by macrophages has been associated with ONOO Ϫ (21), we suggest that impaired parasite growth in AhR KO macrophages is due to the lack of the oxidative signal that was shown to be necessary for parasite growth inside these cells (19,47).…”

Section: Discussionmentioning

confidence: 91%

“…Recently, it was demonstrated that ROS, besides its potent prooxidant effect on intracellular pathogens, can also be beneficial for T. cruzi replication in vitro (35,47). It has been shown that T. cruzi can sequester iron from ferritin upon oxidative burst (19), providing an explanation for the defect in parasite replication observed in AhR KO macrophages.…”

Section: Discussionmentioning

confidence: 99%

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The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

et al. 2016

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eThe aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in controlling several aspects of immune responses, including the activation and differentiation of specific T cell subsets and antigen-presenting cells, thought to be relevant in the context of experimental Trypanosoma cruzi infection. The relevance of AhR for the outcome of T. cruzi infection is not known and was investigated here. We infected wild-type (WT) mice and AhR knockout (AhR KO) mice with T. cruzi (Y strain) and determined levels of parasitemia, myocardial inflammation and fibrosis, expression of AhR/cytokines/suppressor of cytokine signaling (SOCS) (spleen/heart), and production of nitric oxide (NO), reactive oxygen species (ROS), and peroxynitrite (ONOO ؊ ) (spleen). AhR expression was increased in the heart of infected WT mice. Infected AhR KO mice displayed significantly reduced parasitemia, inflammation, and fibrosis of the myocardium. This was associated with an anticipated increased immune response characterized by increased levels of inflammatory cytokines and reduced expression of SOCS2 and SOCS3 in the heart. In vitro, AhR deficiency caused impairment in parasite replication and decreased levels of ROS production. In conclusion, AhR influences the development of murine Chagas disease by modulating ROS production and regulating the expression of key physiological regulators of inflammation, SOCS1 to -3, associated with the production of cytokines during experimental T. cruzi infection. The aryl hydrocarbon receptor (AhR) was originally described as a ligand-dependent transcription factor for exogenous ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) capable of activating the aryl hydrocarbon hydroxylase (1, 2). In humans and mice, AhR recognizes several endogenous ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ), kynurenines, indoles (3, 4), and lipoxins (LX) (5). The activation of the AhR signaling pathway controls the genomic expression of diverse target genes, leading to different physiological outcomes (6). More recently, it has been recognized that AhR is involved in the regulation of several immune processes. The major immune mechanisms controlled by AhR are related to the activation and differentiation of specific T cell subsets (T regulatory [Treg] and Th17) and antigenpresenting cells (3). In the context of immunity to infections, it was demonstrated that AhR is an essential protein for murine resistance to Listeria monocytogenes (7) and toxoplasmosis (8).More recently, we found that it was an important factor in controlling parasitemia and inflammation during experimental cerebral malaria (9). Additionally, it is associated with antiviral immunity (10) and is a negative regulator of inflammatory cytokines in response to Leishmania major experimental infection (11). Taken together, the results of these studies strongly suggest that AhR function during immune responses to infections is complex and likely pathogen specific.Trypanosoma cruzi is a flagellated protozoan parasite that...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

et al. 2016

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“…It is known that during its life cycle T. cruzi is exposed to different redox environments inside the invertebrate and vertebrate hosts [7,8] and the ability of T. cruzi to adapt to the redox state contributes to the success of the infection [9]. Additionally, in terms of a physiological approach, ROS play a vital role in T. cruzi-vector interactions, because heme, a molecule from the insect blood digestion, triggers epimastigote proliferation through a redox-sensitive signaling mechanism [10].…”

Section: The Biological Cycle Of Trypanosoma Cruzimentioning

confidence: 99%

The Journey ofTrypanosoma cruziunder the Redox Baton

Paes¹

2019

Biology OfTrypanosoma Cruzi

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Trypanosoma cruzi is a protozoan responsible for Chagas disease and has a complex life cycle including vertebrate (mammals) and invertebrate (insects) hosts. The parasite presents proliferative and infective forms that are challenged throughout their cycle as different sources of nutrients, pH, immune system, and levels of reactive oxygen species (ROS). Although ROS cause damage to cells and tissues when their levels are controlled, they are involved in signal transduction pathways involved in cell growth and differentiation. Curiously, the proliferation of epimastigote inside the bug insect is favored by high levels of ROS from the digestion of blood meal, and it is regulated by a cellular signaling mechanism involving heme and CaMKII. On the other hand, the differentiation of epimastigote into metacyclic trypomastigote in the rectum occurs in the reduced state. Interestingly, when the parasite infects the vertebrate, the immune system recognizes this pathogen and macrophages become activated. Thus, NADPH oxidase produces ROS that helps the parasite enter the mammalian cells, improving the infection. The parasite thrives inside the mammalian cells also involving ROS. Thus, the life cycle of Trypanosoma cruzi obeys a fine tuning of the redox state, not affecting the host cells and being helpful to the parasite.

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“…Trypanosoma cruzi overexpressing the enzyme EcMutT (from E coli ) or TcMTH (from T cruzi ), which is responsible for removing 8‐oxo‐dGTP from the nucleotide pool, a cellular marker of oxidative stress, indicated that modified parasites presented enhanced replication inside murine inflammatory macrophages from C57BL/6 WT mice when compared with control parasites. Interestingly, when Phox KO macrophages were infected with these parasites, they observed a decreased number of all parasites when compared with macrophages from C57BL/6 WT …”

Section: How Do Neutrophils Participate In the Immunopathogenesis Of mentioning

confidence: 99%

“…Interestingly, when Phox KO macrophages were infected with these parasites, they observed a decreased number of all parasites when compared with macrophages from C57BL/6 WT. 50 Trypanosoma cruzi has a highly efficiently regulated antioxidant machinery to deal with the oxidative burst. Nuclear factor, erythroid-derived 2, like 2 (NRF2) orchestrates antioxidant defences, including the expression of heme-oxygenase-1 (HO-1).…”

Section: Mechanisms That Neutrophils Use To Eliminate and Modulate mentioning

confidence: 99%

Involvement of neutrophils in Chagas disease pathology

Andrade

Almeida

Souza

et al. 2018

Parasite Immunology

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Chagas disease (CD) is a public health problem in Latin America. The acute phase presents nonspecific symptoms and most patients recover from acute parasitemia and undergo a prolonged asymptomatic phase. Several years later, about 30% of infected individuals develop chronic cardiopathy with progressive cardiomegaly, arrhythmia, thromboembolic events and heart failure. These symptoms suggest a persistent association with the presence of inflammatory infiltrate and tissue, and cellular destruction in the heart muscle. Nevertheless, few research studies have attempted to understand the role of inflammatory cells, such as neutrophils, in establishing the pathology and progression of CD. Only recently have some studies been performed with this intention. Despite this effort, the role of neutrophils in CD is still considered controversial. This review discusses the morphological and functional characteristics of neutrophils that describes their participation in the establishment and progression of Trypanosoma cruzi infection, through the development of its effector functions, such as release of lithic components, production of oxidative agents and release of inflammatory mediators capable of modulating the host immune response.

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Trypanosoma cruzi Needs a Signal Provided by Reactive Oxygen Species to Infect Macrophages

Cited by 63 publications

References 81 publications

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

The Aryl Hydrocarbon Receptor Modulates Production of Cytokines and Reactive Oxygen Species and Development of Myocarditis during Trypanosoma cruzi Infection

The Journey ofTrypanosoma cruziunder the Redox Baton

Involvement of neutrophils in Chagas disease pathology

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