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.

Chagas disease is a neglected tropical disease caused by the flagellated protozoa Trypanosome cruzi. This illness affects to almost 8–12 million people worldwide, however, is endemic to Latin American countries. It is mainly vectorially transmitted by insects of the Triatominae family, although other transmission routes also exist. T. cruzi-infected cardiomyocytes at the chronic stage of the disease display severe mitochondrial dysfunction and high ROS production, leading to chronic myocardial inflammation and heart failure. Under cellular stress, cells usually can launch mitochondrial biogenesis in order to restore energy loss. Key players to begin mitochondrial biogenesis are the PGC-1 (PPARγ coactivator 1) family of transcriptional coactivators, which are activated in response to several stimuli, either by deacetylation or dephosphorylation, and in turn can serve as coactivators for the NRF (nuclear respiratory factor) family of transcription factors. The NRF family of transcriptional activators, namely NRF1 and NRF2, can activate gene expression of oxidative phosphorylation (OXPHOS) components, mitochondrial transcriptional factor (Tfam) and nuclear encoded mitochondrial proteins, leading to mitochondrial biogenesis. On the other hand, NRF2 can activate gene expression of antioxidant enzymes in response to antioxidants, oxidants, electrophile compounds, pharmaceutical and dietary compounds in a mechanism dependent on KEAP1 (Kelch-like ECH-associated protein 1). Since a definitive cure to treat Chagas disease has not been found yet; the use of antioxidants a co-adjuvant therapy has been proposed in an effort to improve mitochondrial functions, biogenesis, and the antioxidant defenses response. Those antioxidants could activate different pathways to begin mitochondrial biogenesis and/or cytoprotective antioxidant defenses. In this review we discuss the main mechanisms of mitochondrial biogenesis and the NRF2-KEAP1 activation pathway. We also reviewed the antioxidants used as co-adjuvant therapy to treat experimental Chagas disease and their action mechanisms and finish with the discussion of antioxidant therapy used in Chagas disease patients.

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.

Inflammation and mucus production are prevalent characteristics of chronic respiratory conditions, such as asthma and chronic chronic obstructive pulmonary disease (COPD). Biological co-factors, including bacteria, viruses, and fungi, may exacerbate these diseases by activating various pathways associated with airway diseases. An example is the fungus Pneumocystis, which is linked to severe COPD in human patients. Recent evidence has demonstrated that Pneumocystis significantly enhanced inflammation and mucus hypersecretion in a rat model of elastase-induced COPD. The present study specifically aims to investigate two additional aspects associated with the pathology induced by Pneumocystis infection: inflammation and collagen deposition around airways. To this end, the focus was to investigate the role of the IL-1β pro-inflammatory pathway during Pneumocystis infection in COPD rats. Several airway pathology-related features, such as inflammation, mucus hypersecretion, and fibrosis, were evaluated using histological and molecular techniques. COPD animals infected with Pneumocystis exhibited elevated inflammation levels, including a synergistic increase in IL-1β and Cox-2. Furthermore, protein levels of the IL-1β-dependent transcription factor cAMP response element-binding (CREB) showed a synergistic elevation of their phosphorylated version in the lungs of COPD animals infected with Pneumocystis, while mucus levels were notably higher in the airways of COPD-infected animals. Interestingly, a CREB responsive element (CRE) was identified in the Muc5b promoter. The presence of CREB in the Muc5b promoter was synergistically increased in COPD animals infected with Pneumocystis compared to other experimental groups. Finally, an increment of deposited collagen was identified surrounding the airways of COPD animals infected with Pneumocystis compared with the other experimental animal groups and correlated with the increase of Tgfβ1 mRNA levels. These findings emphasize the role of Pneumocystis as a potential biological co-factor in chronic respiratory diseases like COPD or asthma, warranting new perspectives in the treatment of chronic respiratory diseases.

Inflammation and mucus hypersecretion are frequent pathology features of chronic respiratory diseases such as asthma and COPD. Selected bacteria, viruses and fungi may synergize as co-factors in aggravating disease by activating pathways that are able to induce airway pathology. Pneumocystis infection induces inflammation and mucus hypersecretion in immune competent and compromised humans and animals. This fungus is a frequent colonizer in patients with COPD. Therefore, it becomes essential to identify whether it has a role in aggravating COPD severity. This work used an elastase-induced COPD model to evaluate the role of Pneumocystis in the exacerbation of pathology, including COPD-like lung lesions, inflammation and mucus hypersecretion. Animals infected with Pneumocystis developed increased histology features of COPD, inflammatory cuffs around airways and lung vasculature plus mucus hypersecretion. Pneumocystis induced a synergic increment in levels of inflammation markers (Cxcl2, IL6, IL8 and IL10) and mucins (Muc5ac/Muc5b). Levels of STAT6-dependent transcription factors Gata3, FoxA3 and Spdef were also synergically increased in Pneumocystis infected animals and elastase-induced COPD, while the levels of the mucous cell-hyperplasia transcription factor FoxA2 were decreased compared to the other groups. Results document that Pneumocystis is a co-factor for disease severity in this elastase-induced-COPD model and highlight the relevance of STAT6 pathway in Pneumocystis pathogenesis.

The unicellular protozoan Trypanosoma cruzi is the causing agent of Chagas disease which affects several millions of people around the world. The components of the cell signaling pathways in this parasite have not been well studied yet, although its genome can encode several components able to transduce the signals, such as protein kinases and phosphatases. In a previous work we have found that DNA polymerase β (Tcpolβ) can be phosphorylated in vivo and this modification activates the synthesis activity of the enzyme. Tcpolβ is kinetoplast-located and is a key enzyme in the DNA base excision repair (BER) system. The polypeptide possesses several consensus phosphorylation sites for several protein kinases, however, a direct phosphorylation of those sites by specific kinases has not been reported yet. Tcpolβ has consensus phosphorylation sites for casein kinase 1 (CK1), casein kinase 2 (CK2) and aurora kinase (AUK). Genes encoding orthologues of those kinases exist in T. cruzi and we were able to identify the genes and to express them to investigate whether or no Tcpolβ could be a substrate for in vitro phosphorylation by those kinases. Both CK1 and TcAUK1 have auto-phosphorylation activities and they are able to phosphorylate Tcpolβ. CK2 cannot perform auto-phosphorylation of its subunits, however, it was able to phosphorylate Tcpolβ. Pharmacological inhibitors used to inhibit the homologous mammalian kinases can also inhibit the activity of T. cruzi kinases, although, at higher concentrations. The phosphorylation events carried out by those kinases can potentiate the DNA polymerase activity of Tcpolβ and it is discussed the role of the phosphorylation on the DNA polymerase and lyase activities of Tcpolβ. Taken altogether, indicates that CK1, CK2 and TcAUK1 can play an in vivo role regulating the function of Tcpolβ.