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Correlation analysis between plasma IL-10 levels and cardiac function variables (LVEF and LVDD) in the IND (n = 82, first column) and CARD (n = 94, second column) groups. Correlation analysis was performed using the Spearman correlation coefficient, and results were considered significant when P<0.05. Significant differences (P-value) are indicated in each graph together with the r value.
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The expression of immune response appears to be associated with morbidity in Chagas disease. However, the studies in this field have usually employed small samples of patients and statistical analyses that do not consider the wide dispersion of cytokine production observed in these patients. The aim of this study was to evaluate the plasma cytokine...
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Chagas disease is caused by Trypanosoma cruzi and can lead to a dilated cardiomyopathy decades after the prime infection by the parasite. As with other dilated cardiomyopathies, conventional pharmacologic therapies are not always effective and as heart failure progresses patients need heart transplantation. Therefore alternative therapies are highl...
The role of CD25+ regulatory T cells during the course of Trypanosoma cruzi infection has been previously analyzed, and the bulk of results have shown a limited role for this T cell subpopulation. In this study, we have used an IgM, nondepleting monoclonal antibody (mAb) aiming at blocking interleukin (IL)-2 activity on CD25+ T cells. The administr...
Citations
... These observations align with a deficiency in the regulatory arm of the immune response in CCC. [17][18][19][20] The increased proportion of circulating Th1-T cells is reflected in CCC myocardium. IFN-γ is the most upregulated cytokine 21 and the top upstream regulator of the gene expression profile in CCC heart tissue. ...
This review article highlights the significant impact of mitochondrial dysfunction on Chagas disease (CD) cardiomyopathy. By examining the existing body of research, it provides a comprehensive anal- ysis of the detrimental consequences resulting from impaired mitochondrial function in this cardiac con- dition. We review new intricate relationship between CD cardiomyopathy, inflammatory response, mito- chondrial dysfunction and energy disbalance, elucidating some molecular mechanisms and pathways involved. This review not only enhances our understanding of the disease pathogenesis but also emphasizes the crucial role of mitochondria in cardiac function and its potential as a therapeutic target for mitigating CD cardiomyopathy.
... Similar reductions in IFN-ɣ production have been observed after etiological treatment of children in the recent chronic phase of CD, indicating a decrease in stimulation by T. cruzi antigens [65]. Moreover, the decrease in IFN-ɣ production have been observed in chronic CD patients is considered a favourable prognostic marker, as the excessive increase in this cytokine is associated with the development of severe manifestation of CCC, and a higher risk of sudden death [66][67][68]. ...
... On the other hand, there is some information about cytokines expression in plasma or serum and its association with Chagas cardiomyopathy. In the largest study, with 176 patients, IL-10 expression was higher in the indeterminate form, while inflammatory cytokine expression (such as IFN-γ, TNF-α, IL-6 and IL-1β) proved to be the highest in the cardiac form (Sousa et al. 2014;Vasconcelos et al. 2015). Another study showed that lower serum IL-10 levels could be associated with a severely impaired cardiac function (Vasconcelos et al. 2015). ...
... On the other hand, Sousa et al. (Sousa et al. 2014) studied cytokine levels in 82 patients with indeterminate Chagas and 94 with dilated Chagas cardiomyopathy. The individuals with an indeterminate state had higher IL-10 expression, whereas the Chagas cardiomyopathy group presented the highest inflammatory cytokine expression (IFN-γ, TNF-α, IL-6 and IL-1β). ...
Immunoregulatory networks may have a role in controlling parasitemia in the chronic phase of human Chagas disease. The aim was to describe the serum cytokine profile of Trypanosoma cruzi in chronically infected patients and to evaluate its relationship with parasitemia and Chagas cardiomyopathy.
This prospective observational study included adult patients with chronic Chagas disease. Demographic and clinical data were collected, and peripheral blood samples were used to perform T. cruzi real-time polymerase chain reaction (RT-PCR) and determine the serum cytokine profile.
Fifty-eight patients were included; 17 (29.3%) had positive RT-PCR results. This group had a higher median concentration of TNF-α (p = 0.003), IL-6 (p = 0.021), IL-4 (p = 0.031), IL-1β (p = 0.036), and IL-17A (p = 0.043) than those with a negative RT-PCR. Patients with cardiac involvement had a higher median concentration of IL-5 (p = 0.016) than those without.
These results reinforce the key role that cytokines play in Chagas disease patients with parasitemia and cardiac involvement.
... However, low-grade parasites are still present and stimulate the production of IFN-γ, Tumor Necrosis Factor Alpha (TNF-α), and other inflammatory cytokines. 11 It is also worth highlighting that the pro-inflammatory response to T. cruzi infection is dependent on the activation of the Toll-like receptor 4 (TLR4) receptor, which leads, as demonstrated in vitro, to the activation of NF-κB, an important transcription factor for the expression of genes that lead to the release of cytokines and adhesion molecules. 12 Other important mechanisms for the immunological response to infection are the activation of the alternative pathway of the complement system by the epimastigote form of T. cruzi, greater recruitment of NK cells, which promote a cytotoxic effect and are responsible for producing IFN-γ, TNF-α, and opsonization by antibodies. ...
... However, previous studies have linked IL-1 to impaired systolic and diastolic function through various pathways [28]. Other biomarkers such as IFNγ, TNF-α, IL-6, and IL-1β have been investigated, and higher levels have been found in patients with Chagasic cardiac disease in other patient cohorts, which contradicts the findings of this current study [28,30,31]. Similarly, elevated expression of IFN-γ has been observed in serum samples from Chagas disease patients with cardiomyopathy compared to those with the indeterminate form [32]. On the other hand, IL-10 expression has been associated with better cardiac function based on left ventricular ejection fraction and left ventricular diastolic diameter values [32,33]. ...
... When comparing our cohort with other studies, it is important to note that our study included only patients with CCM and significant ventricular dysfunction, whereas the previously discussed studies had different patient characteristics [31][32][33]. Our cohort consisted mainly of functional class II and III patients, who were younger and had lower BNP levels. ...
... Additionally, most of the other studies were cross-sectional or retrospective, despite having a larger sample size. Therefore, the specific characteristics of our study population, including patients with CCM and significant ventricular dysfunction, may explain the discrepancies in inflammatory biomarker findings compared to other studies [31,34]. ...
Background
Chagas disease, endemic in Latin America and spreading globally due to emigration, has a significant health burden, particularly in relation to chagasic heart failure (HF). Chagasic cardiomyopathy (CCM) is characterized by chronic inflammatory myocardial disease. This study aimed to identify inflammatory parameters and biomarkers that could aid in the management of patients with chagasic HF.
Methods and findings
A cohort study was conducted at a tertiary cardiology single-center over a mean follow-up period of 2.4 years. The study included patients with HF secondary to CCM enrolled between October 2013 and July 2017. Various clinical parameters, echocardiography findings, parasitemia status, brain natriuretic peptide (BNP) and troponin T (TnT) levels, and inflammatory biomarkers (IL-6, IL-10, IL-12p70, IL-17A, adiponectin, and IFN-γ) were assessed. The study encompassed a cohort of 103 patients, with a median age of 53 years and 70% being male. The left ventricular ejection fraction (LVEF) was 28%, with 40% of patients classified as NYHA II functional class. The median BNP level was 291 pg/ml. The observed mortality rate during the study period was 38.8%. Predictors of lower survival were identified as elevated levels of BNP, TnT, reduced LVEF, and increased adiponectin (thresholds: BNP > 309 pg/ml, TnT > 27.5 ng/ml, LVEF < 25.5%, adiponectin > 38 μg/mL). Notably, there was no evidence indicating a relationship between parasitemia and the inflammatory parameters with lower survival in these patients, including INF-γ, IL-6, IL-10, IL12-(p70), and IL17a.
Conclusion
Despite the presence of a chronic inflammatory process, the evaluated inflammatory biomarkers in this cohort were not predictive of survival in patients with chagasic HF with reduced ejection fraction (HFrEF). However, reduced LVEF, elevated BNP, adiponectin levels, and troponin T were identified as predictors of lower survival in these patients.
... These observations align with a deficiency in the regulatory arm of the immune response in CCC. [17][18][19][20] The increased proportion of circulating Th1-T cells is reflected in CCC myocardium. IFN-γ is the most upregulated cytokine 21 and the top upstream regulator of the gene expression profile in CCC heart tissue. ...
Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is a neglected disease affecting around 6 million people. About 30% of CD patients develop chronic Chagas disease cardiomyopathy (CCC), an inflammatory cardiomyopathy that occurs decades after the initial infection, while most infected patients (60%) remain asymptomatic in the so-called indeterminate form (IF). Death results from heart failure or arrhythmia in a subset of CCC patients. Myocardial fibrosis, inflammation, and mitochondrial dysfunction are involved in the arrhythmia substrate and triggering events. Survival in CCC is worse than in other cardiomyopathies, which may be linked to a Th1-T cell rich myocarditis with abundant interferon (IFN)-γ and tumor necrosis factor (TNF)-α, selectively lower levels of mitochondrial energy metabolism enzymes in the heart, and reduced levels of high-energy phosphate, indicating poor adenosine triphosphate (ATP) production. IFN-γ and TNF-α signaling, which are constitutively upregulated in CD patients, negatively affect mitochondrial function in cardiomyocytes, recapitulating findings in CCC heart tissue. Genetic studies such as whole-exome sequencing (WES) in nuclear families with multiple CCC/IF cases has disclosed rare heterozygous pathogenic variants in mitochondrial and inflammatory genes segregating in CCC cases. In this minireview, we summarized studies showing how IFN-γ and TNF-α affect cell energy generation, mitochondrial health, and redox homeostasis in cardiomyocytes, in addition to human CD and mitochondria. We hypothesize that cytokine-induced mitochondrial dysfunction in genetically predisposed patients may be the underlying cause of CCC severity and we believe this mechanism may have a bearing on other inflammatory cardiomyopathies.
... Patients without overt clinical disease exhibit a mixed T H 1/ T H 2/T H 17 immune profile, with increased levels of the key cytokines IFNγ, IL-10, and IL-17. In contrast, patients with clinical signs of cardiomyopathy have a predominantly T H 1 immune profile, with increased levels of the pro-inflammatory cytokines IFNγ, IL-6, TNFα, and IL-1β and very little IL-10 and IL-17 [16][17][18][19][20] . ...
... Given the association between CD and immune responses 16 and the poor tolerability of standard BNZ treatment regimens in humans 46,47 , we then assessed whether an experimental regimen consisting of a combination of reduced-dose BNZ (25 mg/kg for 18 days) followed by two doses of a therapeutic vaccine, Tc24-C4 (25 μg at 92 and 106 DPI), could provide a phenotypic and small molecule benefit. This therapeutic vaccine has previously been shown to improve cardiac fibrosis and cellular infiltration 48 . ...
Post-infectious conditions present major health burdens but remain poorly understood. In Chagas disease (CD), caused by Trypanosoma cruzi parasites, antiparasitic agents that successfully clear T. cruzi do not always improve clinical outcomes. In this study, we reveal differential small molecule trajectories between cardiac regions during chronic T. cruzi infection, matching with characteristic CD apical aneurysm sites. Incomplete, region-specific, cardiac small molecule restoration is observed in animals treated with the antiparasitic benznidazole. In contrast, superior restoration of the cardiac small molecule profile is observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy, even with less parasite burden reduction. Overall, these results reveal molecular mechanisms of CD treatment based on simultaneous effects on the pathogen and on host small molecule responses, and expand our understanding of clinical treatment failure in CD. This link between infection and subsequent persistent small molecule perturbation broadens our understanding of infectious disease sequelae.
... Invasion of parasites into cardiomyocytes causes cellular hypertrophy and recruitment of inflammatory cells into tissues, including macrophages, neutrophils, CD4+ and CD8+ T cells (Higuchi Mde et al., 1993;Higuchi et al., 1997). Pro-inflammatory cytokines, including IFNg, TNFa and IL-6, are elevated in cardiac tissue and in the serum of patients with CCC and correlate with disease severity (Reis et al., 1997;Laucella et al., 2004;Guedes et al., 2012;Magalhães et al., 2013;Sousa et al., 2014;Sousa et al., 2017). Additionally, a recent study showed that CD4+CD25 high Foxp3+ regulatory T cells (Tregs) were significantly reduced, while cytotoxic CD4+ cells were significantly increased in CCC patients compared to healthy controls (Almeida et al., 2022). ...
Introduction
Hookworms are parasitic helminths that secrete a variety of proteins that induce anti-inflammatory immune responses, stimulating increased CD4+Foxp3+ regulatory T cells and IL-10 production. Hookworm-derived recombinant proteins AIP-1 and AIP-2 have been shown to reduce inflammation in mouse models of inflammatory bowel disease and inflammatory airway disease by inducing CD4+Foxp3+ cells and IL-10 production. In contrast, chronic infection with the protozoal parasite Trypanosoma cruzi , the causative agent of Chagas disease, leads to chronic inflammation in tissues. Persistence of the parasites in tissues drives chronic low-grade inflammation, with increased infiltration of inflammatory cells into the heart, accompanied by increased production of inflammatory cytokines. There are no current antiparasitic drugs that effectively reduce or prevent chronic myocarditis caused by the onset of Chagas disease, thus new therapies are urgently needed. Therefore, the impact of AIP-1 and AIP-2 on myocarditis was investigated in a mouse model of chronic T. cruzi infection.
Methods
Female BALB/c mice infected with bioluminescent T. cruzi H1 strain trypomastigotes for 70 days were treated once daily for 7 days with 1mg/kg AIP-1 or AIP-2 protein by intraperitoneal injection. Control mice were left untreated or treated once daily for 14 days with 25mg/kg aspirin in drinking water. At 84 days of infection, splenocytes, cardiac tissue and serum were collected for evaluation.
Results
Treatment with both AIP-1 and AIP-2 proteins significantly reduced cardiac cellular infiltration, and reduced cardiac levels of IFNγ, IL-6 and IL-2. AIP-2 treatment reduced cardiac expression of COX-2. Further, while incubation with AIP-1 and AIP-2 proteins did not induce a significant upregulation of an immunoregulatory phenotype in dendritic cells (DC), there was a modest upregulation of CD11c+CD11b+MHCII+SIRPα+ expression, suggesting a regulatory phenotype. Ex-vivo stimulation of splenocytes from the treatment groups with AIP-1 loaded DC induced reduced levels of cytotoxic and pro-inflammatory T cells, stimulation with AIP-2 loaded DC specifically induced enhanced levels of CD4+CD25+Foxp3+ regulatory T cells among treatment groups.
Discussion
All in vivo and in vitro results demonstrate that hookworm-derived AIP-1 and AIP-2 proteins reduce T. cruzi induced cardiac inflammation, possibly through multiple anti-inflammatory mechanisms.
... The study conducted by Sousa et al. 21 on patients with CD showed that higher expression of IL-10 is linked to better cardiac function. ...
Chagas disease is caused by the Trypanosoma cruzi parasite and is transmitted by infected triatomine bugs. This infection affects approximately 8 million people in the Americas, and due to globalisation and displacement, it is becoming increasingly common to find infected patients worldwide. Diagnosis of the disease in its acute form is relatively simple, as the parasite can be detected in peripheral blood smears, and symptoms are visible. However, in its chronic condition, the parasite is almost undetectable , and indirect tests are necessary to determine the presence of antibodies in infected patients. It is important to note that a single test is not enough to confirm the disease in this phase, as a second serological test should confirm the diagnosis. If the results are contradictory, a third test should be performed to confirm or discard the disease. Unfortunately, laboratories may not have access to all necessary tests in many rural areas where the disease is more frequent. Rapid tests to diagnose this disease present problems, such as significant variations in sensitivity and specificity in different countries. Therefore, searching for new biomarkers that allow for optimal correlation is essential. In this work, we have searched scientific literature from the last 10 years for mentions of novel biomarkers for diagnosis, treatment follow-up, and prediction of cardiac complications in Chagas disease in its chronic phase.
... The hPEK were infected at a MOI of 3:1 or stimulated with 0.1 ng/ml and 10 ng/ml of IFN-γ respectively. IFN-γ was chosen due to its crucial role in T. cruzi infection in murine models (13) and also chronic Chagas patients (14). We The fraction of cells expressing MIC-A/B and Galectin-9 was also higher compared to untreated controls but did not reach statistically significance (S6 B, C). ...
Infection with the protozoan parasite Trypanosoma cruzi is causative for Chagas disease, which is a highly neglected tropical disease prevalent in Latin America. Humans are primary infected through vectorial transmission by blood-sucking triatomine bugs. The parasite enters the human host through mucous membranes or small skin lesions. Since keratinocytes are the predominant cell type in the epidermis, they play a critical role in detecting disruptions in homeostasis and aiding in pathogen elimination by the immune system in the human skin as alternative antigen-presenting cells. Interestingly, keratinocytes also act as a reservoir for T. cruzi, as the skin has been identified as a major site of persistent infection in mice with chronic Chagas disease. Moreover, there are reports of the emergence of T. cruzi amastigote nests in the skin of immunocompromised individuals who are experiencing reactivation of Chagas disease. This observation implies that the skin may serve as a site for persistent parasite presence during chronic human infection too and underscores the significance of investigating the interactions between T. cruzi and skin cells. Consequently, the primary objective of this study was to establish and characterize the infection kinetics in human primary epidermal keratinocytes (hPEK). Our investigation focused on surface molecules that either facilitated or hindered the activation of natural killer (NK) cells, which play a crucial role in controlling the infection. To simulate the in vivo situation in humans, an autologous co-culture model was developed to examine the interactions between T. cruzi infected keratinocytes and NK cells. We evaluated the degranulation, cytokine production, and cytotoxicity of NK cells in response to the infected keratinocytes. We observed a strong activation of NK cells by infected keratinocytes, despite minimal alterations in the expression of activating or inhibitory ligands on NK cell receptors. However, stimulation with recombinant interferon-gamma (IFN-γ), a cytokine known to be present in significant quantities during chronic T. cruzi infections in the host, resulted in a substantial upregulation of these ligands on primary keratinocytes. Overall, our findings suggest the crucial role of NK cells in controlling acute T. cruzi infection in the upper layer of the skin and shed light on keratinocytes as potential initial targets of infection.
