Cyclophilin 19 secreted in the host cell cytosol by<i>Trypanosoma cruzi</i>promotes<scp>ROS</scp>production required for parasite growth

Santos, Gregory Pedroso Dos; Abukawa, Fernanda Midori; Souza-Melo, Normanda; Alcântara, Laura Maria; Bittencourt‐Cunha, Paula; Moraes, Carolina Borsoi; Jha, Bijay Kumar; McGwire, Bradford S.; Moretti, Nilmar Silvio; Schenkman, Sérgio

doi:10.1111/cmi.13295

Cited by 9 publications

(17 citation statements)

References 65 publications

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“…ROS can also act as key regulators of parasite control by means of regulating cytokine responses and also splenic inflammatory cell proliferation during the infection [ 20 ]. However, recent evidence indicates that ROS can provide a positive signal for T. cruzi cell proliferation [ 22 ].…”

Section: Inflammation and Oxidative Damage In Chagas Diseasementioning

confidence: 99%

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

Maldonado

Rojas

Urbina

et al. 2021

Oxidative Medicine and Cellular Longevity

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Chagas disease is a neglected tropical disease caused by the flagellated protozoa Trypanosoma cruzi that affects several million people mainly in Latin American countries. Chagas disease has two phases, which are acute and chronic, both separated by an indeterminate time period in which the infected individual is relatively asymptomatic. The acute phase extends for 40-60 days with atypical and mild symptoms; however, about 30% of the infected patients will develop a symptomatic chronic phase, which is characterized by either cardiac, digestive, neurological, or endocrine problems. Cardiomyopathy is the most important and severe result of Chagas disease, which leads to left ventricular systolic dysfunction, heart failure, and sudden cardiac death. Most deaths are due to heart failure (70%) and sudden death (30%) resulting from cardiomyopathy. During the chronic phase, T. cruzi-infected macrophages respond with the production of proinflammatory cytokines and production of superoxide and nitric oxide by the NADPH oxidase 2 (NOX2) and inducible nitric oxide synthase (iNOS) enzymes, respectively. During the chronic phase, myocardial changes are produced as a result of chronic inflammation, oxidative stress, fibrosis, and cell death. The cellular inflammatory response is mainly the result of activation of the NF-κB-dependent pathway, which activates gene expression of inflammatory cytokines, leading to progressive tissue damage. The persisting production of reactive oxygen species (ROS) is the result of mitochondrial dysfunction in the cardiomyocytes. In this review, we will discuss inflammation and oxidative damage which is produced in the heart during the chronic phase of Chagas disease and recent evidence on the role of macrophages and the production of proinflammatory cytokines during the acute phase and the origin of macrophages/monocytes during the chronic phase of Chagas disease. We will also discuss the contributing factors and mechanisms leading to the chronic inflammation of the cardiac tissue during the chronic phase of the disease as well as the innate and adaptive host immune response. The contribution of genetic factors to the progression of the chronic inflammatory cardiomyopathy of chronic Chagas disease is also discussed. The secreted extracellular vesicles (exosomes) produced for both T. cruzi and infected host cells can play key roles in the host immune response, and those roles are described. Lastly, we describe potential treatments to attenuate the chronic inflammation of the cardiac tissue, designed to improve heart function in chagasic patients.

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Section: Inflammation and Oxidative Damage In Chagas Diseasementioning

confidence: 99%

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

Maldonado

Rojas

Urbina

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…However, other reports show that T. cruzi needs a signal provided by ROS to infect macrophages (Goes et al, 2016). In the same direction, cyclophilin 19 released in the host cell cytosol by T. cruzi mediates the increase of ROS, required to boost parasite proliferation in mammalian hosts (Dos Santos et al, 2021).…”

Section: Host-derived Rns and Ros In Trypanosoma Cruzi Infectionmentioning

confidence: 98%

Myeloid-Derived Suppressor Cells in Trypanosoma cruzi Infection

Fresno

Gironès

2021

Front. Cell. Infect. Microbiol.

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Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous myeloid cells that expand in pathologic conditions as cancer, trauma, and infection. Although characterization of MDSCs is continuously revisited, the best feature is their suppressor activity. There are many markers for MDSC identification, it is distinctive that they express inducible nitric oxide synthase (iNOS) and arginase 1, which can mediate immune suppression. MDSCs can have a medullary origin as a result of emergency myelopoiesis, but also can have an extramedullary origin. Early studies on Trypanosoma cruzi infection showed severe immunosuppression, and several mechanisms involving parasite antigens and host cell mediators were described as inhibition of IL-2 and IL-2R. Another mechanism of immunosuppression involving tumor necrosis factor/interferon γ-dependent nitric oxide production by inducible nitric oxide synthase was also described. Moreover, other studies showed that nitric oxide was produced by CD11b+ Gr-1+ MDSCs in the spleen, and later iNOS and arginase 1 expressed in CD11b+Ly6C+Ly6Glo monocytic MDSC were found in spleen and heart of T. cruzi infected mice that suppressed T cell proliferation. Uncontrolled expansion of monocytic MDSCs leads to L-arginine depletion which hinders nitric oxide production leading to death. Supplement of L-arginine partially reverts L-arginine depletion and survival, suggesting that L-arginine could be administered along with anti-parasitical drugs. On the other hand, pharmacological inhibition of MDSCs leads to death in mice, suggesting that some expansion of MDSCs is needed for an efficient immune response. The role of signaling molecules mediating immune suppression as reactive oxygen species, reactive nitrogen species, as well as prostaglandin E2, characteristics of MDSCs, in T. cruzi infection is not fully understood. We review and discuss the role of these reactive species mediators produced by MDSCs. Finally, we discuss the latest results that link the SLAMF1 immune receptor with reactive oxygen species. Interaction of the parasite with the SLAMF1 modulates parasite virulence through myeloid cell infectivity and reactive oxygen species production. We discuss the possible strategies for targeting MDSCs and SLAMF1 receptor in acute Trypanosoma cruzi infection in mice, to evaluate a possible translational application in human acute infections.

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“…A moderate oxidative environment is advantageous for T. cruzi proliferation ( 69 ) and Chagas disease is known to cause an increase in reactive oxygen species (ROS) in infected tissues and cells ( 70 ). Intracellular T. cruzi forms release in the host cytosol its major cyclophilin of 19 kDa (TcCyp19) ( 71 ). TcCyp19, causes the increase in ROS required for parasite growth in the mammalian host ( 71 ).…”

Section: Immunomodulatory Molecules and Their Mechanisms Of Actionmentioning

confidence: 99%

“…Intracellular T. cruzi forms release in the host cytosol its major cyclophilin of 19 kDa (TcCyp19) ( 71 ). TcCyp19, causes the increase in ROS required for parasite growth in the mammalian host ( 71 ).…”

Section: Immunomodulatory Molecules and Their Mechanisms Of Actionmentioning

confidence: 99%

Parasitomimetics: Can We Utilize Parasite-Derived Immunomodulatory Molecules for Interventions to Immunological Disorders?

Nagai

Goto

2022

Front. Immunol.

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Because our immune system has ability to expel microorganisms invading our body, parasites need evolution to maintain their symbiosis with the hosts. One such strategy of the parasites is to manipulate host immunity by producing immunomodulatory molecules and the ability of parasites to regulate host immunity has long been a target of research. Parasites can not only manipulate host immune response specific to them, but also influence the host’s entire immune system. Such ability of the parasites may sometimes bring benefit to the hosts as many studies have indicated the “hygiene hypothesis” that a decreased opportunity of parasitic infections is associated with an increased incidence of allergy and autoimmune diseases. In other words, elucidating the mechanisms of parasites to regulate host immunity could be applied not only to resolution of parasitic infections but also to treatment of non-parasitic immunological disorders. In this review, we show how much progress has been made in the research on immunomodulation of host immunity by parasites. Here, we define the word ‘parasitomimetics’ as emulation of parasites’ immunomodulatory systems to solve immunological problems in humans and discuss potential applications of parasite-derived molecules to other diseases.

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Cyclophilin 19 secreted in the host cell cytosol byTrypanosoma cruzipromotesROSproduction required for parasite growth

Cited by 9 publications

References 65 publications

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

The Oxidative Stress and Chronic Inflammatory Process in Chagas Disease: Role of Exosomes and Contributing Genetic Factors

Myeloid-Derived Suppressor Cells in Trypanosoma cruzi Infection

Parasitomimetics: Can We Utilize Parasite-Derived Immunomodulatory Molecules for Interventions to Immunological Disorders?

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