Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy

Chevillard, Christophe; Nunes, João Paulo Silva; Frade, Amanda Farage; Almeida, Rafael Ribeiro; Pandey, Ramendra Pati; Nascimento, Marilda Savóia; Kalil, Jorge; Cunha-Neto, Edécio

doi:10.3389/fimmu.2018.02791

Cited by 58 publications

(84 citation statements)

References 150 publications

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“…The pathogenesis of CCC is not fully understood and is likely multifactorial . While parasite persistence is clearly involved, there are relatively low levels of parasite antigen and DNA despite the massive inflammation and fibrosis generally observed in CCC patients . Bystander activation and autoreactivity against cardiac tissue may contribute, but this has still to be formally demonstrated .…”

Section: Introductionmentioning

confidence: 99%

“…7 While parasite persistence is clearly involved, 9 there are relatively low levels of parasite antigen and DNA despite the massive inflammation and fibrosis generally observed in CCC patients. 11,12 Bystander activation and autoreactivity against cardiac tissue may contribute, but this has still to be formally demonstrated. [13][14][15] The current hypothesis is that CCC is mostly a result of inflammatory disease triggered by T. cruzi infection.…”

Section: Introductionmentioning

confidence: 99%

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Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

Roffê

Santos

et al. 2019

Journal of Leukocyte Biology

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The infection with the protozoan parasite Trypanosoma cruzi causes Chagas disease, a neglected tropical disease in Latin America and an imported emerging disease worldwide. Chronic Chagasic cardiomyopathy (CCC), a progressive inflammatory and fibrosing disease, is the most prominent clinical form of Chagas disease, culminating in heart failure and high rates of sudden death. CCC pathogenesis is influenced by both host and parasite factors and is proposed to be mostly immune‐driven. Chemokines are crucial players in orchestrating immune cell recruitment to infected tissues and inflammation. Herein, we investigated inflammatory chemokine receptor expression on circulating T cells in patients stratified by CCC severity. Compared to asymptomatic individuals, we found increased percentages of effector CD4+ T cells and central memory CD4+ and CD8+ T cells expressing CCR5 in patients with structural cardiopathy, but normal global ventricular function and no symptoms of chronic heart failure. Even naïve T cells expressed CCR5 in these patients. In contrast, reduced frequencies of CD4+ and CD8+ effector T cells expressing CXCR3 were observed in patients presenting with severe heart disease. Patients with increased left ventricular diameter, heart enlargement, and insufficiency had higher frequencies of CCR5+ effector and effector memory CD8+ T cells. Moreover, the percentage of effector CCR5+ CD8+ T cells was increased in patients with a reduced ejection fraction. Our results show that high expression CCR5 and low expression of CXCR3 on circulating T cells are associated with worse prognosis, possibly reflecting immune‐mediated cardiac remodeling of CCC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

Roffê

Santos

et al. 2019

Journal of Leukocyte Biology

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“…Association studies offer a potentially powerful approach to identify genetic variations that are involved in the immunopathogenesis of Chagas disease [16][17][18][19] . However, individual genetic association studies frequently have limitations and the results may be specific to the population of the study.…”

Section: Discussionmentioning

confidence: 99%

“…It's well known that, genetic factors and immunologic response may determine the susceptibility against the infection and the outcome of Chagas disease [16][17][18][19] . Thus, polymorphisms in genes encoding cytokines may influence the level of cytokines production and, consequently, cause different immunological responses [20][21][22] .…”

mentioning

confidence: 99%

Genetic polymorphisms of IL17A associated with Chagas disease: results from a meta-analysis in Latin American populations

Strauss

Palma-Vega

Casares-Marfil

et al. 2020

Sci Rep

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Genetic factors and the immunologic response have been suggested to determine the susceptibility against the infection and the outcome of chagas disease. in the present study, we analysed three IL17A genetic variants (rs4711998, rs8193036 and rs2275913) regarding the predisposition to Trypanosoma cruzi infection and the development of chronic Chagas cardiomyopathy (CCC) in different Latin American populations. A total of 2,967 individuals from Colombia, Argentina, Bolivia and Brazil, were included in this study. The individuals were classified as seronegative and seropositive for T. cruzi antigens, and this last group were divided into asymptomatic and ccc. for T. cruzi infection susceptibility, the IL17A rs2275913*A showed a significant association in a fixed-effect meta-analysis after a Bonferroni correction (p = 0.016, OR = 1.21, 95%CI = 1.06-1.41). No evidence of association was detected when comparing ccc vs. asymptomatic patients. However, when ccc were compared with seronegative individuals, it showed a nominal association in the meta-analysis (p = 0.040, oR = 1.20, 95%CI = 1.01-1.45). For the IL17A rs4711998 and rs8193036, no association was observed. in conclusion, our results suggest that IL17A rs2275913 plays an important role in the susceptibility to T. cruzi infection and could also be implicated in the development of chronic cardiomyopathy in the studied Latin American population.Chagas disease caused by the protozoan Trypanosoma cruzi is a parasitic infection endemic in Latin American countries, which is nowadays increasingly becoming a global health problem, due to migration to non-endemic areas 1,2 . Around 6 to 7 million people are estimated to be infected worldwide, mostly in Latin America 1,3 . During the acute phase of the disease, the increase of parasitic load induces an inflammatory process for the control of the pathogen 4 . Ten to thirty years after infection, around 30 to 40% of chronically infected patients can develop cardiomyopathy or/and megaviscera. The symptoms include cardiac conduction abnormalities, myocardial contractile dysfunction, arrhythmias, dysphagia, regurgitation, and severe constipation, among others. The cardiac involvement is the most frequent manifestation of the disease 5,6 . The characteristics of this phase vary in different patients and in different regions of the endemic area 7 .After the infection with T. cruzi, interleukin-17A (IL-17A) is produced by T helper 17 (Th17) cells, subset of CD4+ T cells, and innate lymphoid cells 8,9 . More recently, it has been described that B cells are also an important source of IL-17A and IL-17F, produced as well after T. cruzi infection 10,11 . In response to the infection, IL17-A, induces a rapid proinflammatory cascade of chemokines and cytokines that facilitates the recruitment and activation of neutrophils and monocytes required for the early control of the pathogen by the immune system 12,13 . In the chronic phase of the disease, several studies suggest that the clinical progression of Chagas cardiomyopathy involves th...

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“…The absence of any symptoms as well as the inflammatory mechanisms leading to tissue damage is attributed mainly to the immune response developed by the host against the parasite, and to the different means by which the parasite avoids it and persists. Several reports demonstrate a predominance of a humoral and cellular pro-inflammatory environment in cardiac patients, while an anti-inflammatory response seems to prevail in infected subjects without cardiac manifestation (2)(3)(4).…”

Section: Introductionmentioning

confidence: 99%

Altered frequency of CD24^highCD38^high transitional B cells in patients with cardiac involvement of chronic Chagas disease

Acevedo

et al. 2019

Preprint

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The cardiomyopathy developed by patients with chronic Chagas disease (CCD), one of the most severe consequences of T. cruzi infection, is mainly associated with an imbalance between an excessive inflammatory reaction and a defective immunomodulatory profile cause by host-parasite interaction. Despite the growing importance of the regulatory function of B-cells in many malignancies, few studies have addressed their immunosuppressive role in chronic Chagas disease. In this work, we tackled this issue by studying the proportion of different B cell subpopulations and their capacity to secrete IL-10 in individuals with distinct clinical forms of CCD. Seven-colour flow cytometry was performed to examine the peripheral blood B cell compartment in chronic Chagas disease (CCD) patients with and without cardiac manifestations (n=10 for each group) and non-infected donors (n=9). Peripheral blood mononuclear cells (PBMC)were incubated for 5h with PMA, ionomicyn and brefeldin A. According to the expression of markers CD24, CD38 and CD27 showed an expansion of total B cell and transitional CD24 high CD38 high B cell subsets in CCD patients and non-infected donors. Furthermore, although no differences were observed in the frequency of total IL-10 producing B cells (B10) among the groups, CCD patients with cardiac involvement showed an increased proportion of transitional and naïve B10 cells compared to non-infected donors. These findings suggest that immature transitional CD24 high CD38 high B cells are greatly expanded in patients with the cardiac form of chronic Chagas disease and these cells retain their ability to secrete IL-10 compared to non-infected donors. Furthermore, the distribution of naïve, transitional and memory B cells inside the B10 cells followed the same pattern in chronic patients without cardiac involvement and non-infected individuals. Our work provides insight into the phenotypic distribution of regulatory B cell in CCD, an important step towards new strategies to prevent cardiomiopathy associated with T. cruzi infection.

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Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy

Cited by 58 publications

References 150 publications

Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

Genetic polymorphisms of IL17A associated with Chagas disease: results from a meta-analysis in Latin American populations

Altered frequency of CD24^highCD38^high transitional B cells in patients with cardiac involvement of chronic Chagas disease

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Disease Tolerance and Pathogen Resistance Genes May Underlie Trypanosoma cruzi Persistence and Differential Progression to Chagas Disease Cardiomyopathy

Cited by 58 publications

References 150 publications

Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

Increased frequencies of circulating CCR5+ memory T cells are correlated to chronic chagasic cardiomyopathy progression

Genetic polymorphisms of IL17A associated with Chagas disease: results from a meta-analysis in Latin American populations

Altered frequency of CD24highCD38high transitional B cells in patients with cardiac involvement of chronic Chagas disease

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Altered frequency of CD24^highCD38^high transitional B cells in patients with cardiac involvement of chronic Chagas disease