Immunoregulatory networks in human <scp>C</scp>hagas disease

Dutra, Walderez O.; Menezes, C. A. S.; Magalhães, Luísa Mourão Dias; Gollob, Kenneth J.

doi:10.1111/pim.12107

Cited by 136 publications

(157 citation statements)

References 81 publications

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“…dominant role in pathogenesis. 28,29,31 Investigators have observed that the prevalence of severe Chagas' cardiomyopathy has fallen in areas with effective vector control and postulate that repeated superinfection due to ongoing vector exposure sustains the tissue antigen load and the consequent inflammatory response at a higher chronic level, which promotes cardiac damage. 32 In an experimental model, mice superinfected with the same or a different parasite strain had more frequent severe ECG changes than those infected only once.…”

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confidence: 99%

Chagas’ Disease

2015

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T h e ne w e ngl a nd jou r na l o f m e dicine n engl j med 373;5 nejm.org July 30, 2015 456Review Article C hagas' disease is caused by the protozoan parasite Trypanosoma cruzi, which is transmitted when the infected feces of the triatomine vector are inoculated through a bite site or through an intact mucous membrane of the mammalian host (Fig. 1). 2 Vectorborne transmission is limited to areas of North America, Central America, and South America. Both in endemic and in nonendemic areas, other infection routes include transfusion, organ and bone marrow transplantation, and congenital transmission. Outbreaks attributed to contaminated food or drink have been reported in northern South America, where transmission cycles involving wild vector populations and mammalian reservoir hosts are prominent. 3 Infection is lifelong in the absence of effective treatment. The most important consequence of T. cruzi infection is cardiomyopathy, which occurs in 20 to 30% of infected persons. 4 Epidemiol ogyThe global epidemiologic profile of Chagas' disease is the result of two major forces: domestic vectorborne transmission over the lifetime of the current population of Latin America and large-scale rural-to-urban migration over the past 50 years (Fig. 2). 2,4 The most epidemiologically important vectors live in the cracks in mud walls and thatched roofs of rustic rural houses. Inhabitants of infested houses are repeatedly exposed to the vector and parasite over many years. Stercorarian transmission (i.e., transmission through the feces of an infected vector) is relatively inefficient: the incidence of T. cruzi infection is generally estimated to be less than 1% per year. 6,7 The highest estimated incidence is 4% per year, in the hyperendemic Bolivian Chaco. 8 In an endemic setting, continued transmission over time results in a pattern of increasing prevalence of both infection and cardiomyopathy with increasing age. 8,9 Over the past several decades, millions of infected persons have moved from endemic rural villages to Latin American cities, and hundreds of thousands now live in the United States, Spain, and other countries outside Latin America. 10,11 Latin America has made substantial progress toward the control of Chagas' disease. 4 The estimated global prevalence of T. cruzi infection declined from 18 million in 1991, when the first regional control initiative began, to 5.7 million in

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confidence: 99%

Chagas’ Disease

2015

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“…Approximately 30% of chronically infected patients develop the cardiac form of the disease, which is the major cause of debilities and death due to severe cardiac manifestations . The chronic cardiac form is associated with an increased expression of pro‐inflammatory cytokines; in contrast, the indeterminate chronic form, which presents positive serology but no clinical findings, is associated with the predominance of an anti‐inflammatory phenotype . However, the complexity of factors involved in the cardiomyopathy development is not fully understood …”

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confidence: 99%

Alternative Th17 and CD4⁺CD25⁺FoxP3⁺ cell frequencies increase and correlate with worse cardiac function in Chagas cardiomyopathy

et al. 2018

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Immune homeostasis has been suggested to play an important role in the clinical evolution of chronic Chagas disease; however, the immunopathologic factors involved have not been fully elucidated. Therefore, our study aimed to analyse the frequency of CD4 CD25 FoxP3 cells, classic Th17 cells, alternative Th17 cells and IL-17 B cells from peripheral blood of chronic cardiac patients after in vitro stimulation with Trypanosoma cruzi soluble EPI antigen. Patients were selected and classified according to clinical evaluation of cardiac involvement: mild, B1 (CARD1) (n = 20) and severe, C (CARD2) (n = 11). Patients with the indeterminate form of CD were included as the control group A (IND) (n = 17). Blood samples were collected and cultured in the presence of EPI antigen. Cells frequency and median fluorescence intensity (MFI) were obtained by flow cytometry. Our results showed that only CD4 CD25 FoxP3 , CD4 CD25 FoxP3 , CD4 IL-17 IFN-γ and CD4 IL-17 IFN-γ cells are more frequent in patients with severe cardiac disease and correlate with worse global cardiac function. However, while indeterminate patients demonstrated a positive correlation between CD4 CD25 FoxP3 and CD4 IL-17 IFN-γ Th17 cells, this relationship was not observed in cardiac patients. IL-17 expression by Th17 cells and B cells correlated with disease progression. Altogether our results suggest that the clinical progression of Chagas cardiomyopathy involves worsening of inflammation and impairment of immunoregulatory mechanisms.

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“…The latter is the most common outcome in parasitic infections, where host survival is essential for the parasite [1]. Alternatively, it may trigger an immune response that is insufficient to control the pathogen fully, leading to the establishment of infection.…”

Section: Introductionmentioning

confidence: 99%

“…A predominantly anti-inflammatory cytokine profile is often observed in IND patients, while an inflammatory profile is clearly associated with CARD [1,5]. Tumour necrosis factor (TNF) and interferon (IFN)-g expression have been associated with worse cardiac function [6] and with progression to severe forms of cardiomyopathy, respectively [7,8].…”

Section: Introductionmentioning

confidence: 99%

Specific activation of CD4–CD8– double-negative T cells byTrypanosoma cruzi-derived glycolipids induces a proinflammatory profile associated with cardiomyopathy in Chagas patients

Passos

Magalhães

Soares

et al. 2017

Clinical and Experimental Immunology

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Cardiomyopathy is the most severe outcome of Chagas disease, causing more than 12 000 deaths/year. Immune cells participate in cardiomyopathy development either by direct tissue destruction, or by driving inflammation. We have shown that CD4 CD8 [double-negative (DN)] T cells are major sources of inflammatory and anti-inflammatory cytokines, associated with the cardiac (CARD) and indeterminate (IND) forms of Chagas disease, respectively. Here, we sought to identify Trypanosoma cruzi-derived components that lead to activation of DN T cells in Chagas patients. Glycolipid (GCL), lipid (LIP) and protein-enriched (PRO) fractions derived from trypomastigote forms of T. cruzi were utilized to stimulate cells from IND and CARD patients to determine DN T cell activation by evaluating CD69 and cytokine expression. We observed that GCL, but not LIP or PRO fractions, induced higher activation of DN T cells, especially T cell receptor (TCR)-γδ DN T, from IND and CARD. GCL led to an increase in tumour necrosis factor (TNF) and interleukin (IL)-10 expression by TCR-γδ DN T cells from IND, while inducing IFN-γ expression by TCR-γδ DN T cells from CARD. This led to an increase in the ratio IFN-γ/IL-10 in TCR-γδ DN T cells from CARD, favouring an inflammatory profile. These results identify GCL as the major T. cruzi component responsible for activation of DN T cells in chronic Chagas disease, associated predominantly with an inflammatory profile in CARD, but not IND. These findings may have implications for designing new strategies of control or prevention of Chagas disease cardiomyopathy by modulating the response to GCL.

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Immunoregulatory networks in human Chagas disease

Cited by 136 publications

References 81 publications

Chagas’ Disease

Chagas’ Disease

Alternative Th17 and CD4⁺CD25⁺FoxP3⁺ cell frequencies increase and correlate with worse cardiac function in Chagas cardiomyopathy

Specific activation of CD4–CD8– double-negative T cells byTrypanosoma cruzi-derived glycolipids induces a proinflammatory profile associated with cardiomyopathy in Chagas patients

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Immunoregulatory networks in human Chagas disease

Cited by 136 publications

References 81 publications

Chagas’ Disease

Chagas’ Disease

Alternative Th17 and CD4+CD25+FoxP3+ cell frequencies increase and correlate with worse cardiac function in Chagas cardiomyopathy

Specific activation of CD4–CD8– double-negative T cells byTrypanosoma cruzi-derived glycolipids induces a proinflammatory profile associated with cardiomyopathy in Chagas patients

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Alternative Th17 and CD4⁺CD25⁺FoxP3⁺ cell frequencies increase and correlate with worse cardiac function in Chagas cardiomyopathy