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      An Animal Model of Acute and Chronic Chagas Disease With the Reticulotropic Y Strain of Trypanosoma cruzi That Depicts the Multifunctionality and Dysfunctionality of T Cells

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          Abstract

          Chagas disease (ChD), a complex and persistent parasitosis caused by Trypanosoma cruzi, represents a natural model of chronic infection, in which some people exhibit cardiac or digestive complications that can result in death 20–40 years after the initial infection. Nonetheless, due to unknown mechanisms, some T. cruzi-infected individuals remain asymptomatic throughout their lives. Actually, no vaccine is available to prevent ChD, and treatments for chronic ChD patients are controversial. Chronically T. cruzi-infected individuals exhibit a deterioration of T cell function, an exhaustion state characterized by poor cytokine production and increased inhibitory receptor co-expression, suggesting that these changes are potentially related to ChD progression. Moreover, an effective anti-parasitic treatment appears to reverse this state and improve the T cell response. Taking into account these findings, the functionality state of T cells might provide a potential correlate of protection to detect individuals who will or will not develop the severe forms of ChD. Consequently, we investigated the T cell response, analyzed by flow cytometry with two multicolor immunofluorescence panels, to assess cytokines/cytotoxic molecules and the expression of inhibitory receptors, in a murine model of acute (10 and 30 days) and chronic (100 and 260 days) ChD, characterized by parasite persistence for up to 260 days post-infection and moderate inflammation of the colon and liver of T. cruzi-infected mice. Acute ChD induced a high antigen-specific multifunctional T cell response by producing IFN-γ, TNF-α, IL-2, granzyme B, and perforin; and a high frequency of T cells co-expressed 2B4, CD160, CTLA-4, and PD-1. In contrast, chronically infected mice with moderate inflammatory infiltrate in liver tissue exhibited monofunctional antigen-specific cells, high cytotoxic activity (granzyme B and perforin), and elevated levels of inhibitory receptors (predominantly CTLA-4 and PD-1) co-expressed on T cells. Taken together, these data support our previous results showing that similar to humans, the T. cruzi persistence in mice promotes the dysfunctionality of T cells, and these changes might correlate with ChD progression. Thus, these results constitute a model that will facilitate an in-depth search for immune markers and correlates of protection, as well as long-term studies of new immunotherapy strategies for ChD.

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          Most cited references 77

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          Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major.

          CD4+ T cells have a crucial role in mediating protection against a variety of pathogens through production of specific cytokines. However, substantial heterogeneity in CD4+ T-cell cytokine responses has limited the ability to define an immune correlate of protection after vaccination. Here, using multiparameter flow cytometry to assess the immune responses after immunization, we show that the degree of protection against Leishmania major infection in mice is predicted by the frequency of CD4+ T cells simultaneously producing interferon-gamma, interleukin-2 and tumor necrosis factor. Notably, multifunctional effector cells generated by all vaccines tested are unique in their capacity to produce high amounts of interferon-gamma. These data show that the quality of a CD4+ T-cell cytokine response can be a crucial determinant in whether a vaccine is protective, and may provide a new and useful prospective immune correlate of protection for vaccines based on T-helper type 1 (TH1) cells.
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            Development of a real-time PCR assay for Trypanosoma cruzi detection in blood samples.

            The aim of this study was to develop a real-time PCR technique to detect Trypanosoma cruzi DNA in blood of chagasic patients. Analytical sensitivity of the real-time PCR was assessed by two-fold serial dilutions of T. cruzi epimastigotes in seronegative blood (7.8 down to 0.06 epimastigotes/mL). Clinical sensitivity was tested in 38 blood samples from adult chronic chagasic patients and 1 blood sample from a child with an acute congenital infection. Specificity was assessed with 100 seronegative subjects from endemic areas, 24 seronegative subjects from non-endemic area and 20 patients with Leishmania infantum-visceral leishmaniosis. Real-time PCR was designed to amplify a fragment of 166 bp in the satellite DNA of T. cruzi. As internal control of amplification human RNase P gene was coamplified, and uracil-N-glycosylase (UNG) was added to the reaction to avoid false positives due to PCR contamination. Samples were also analysed by a previously described nested PCR (N-PCR) that amplifies the same DNA region as the real-time PCR. Sensitivity of the real-time PCR was 0.8 parasites/mL (50% positive hit rate) and 2 parasites/mL (95% positive hit rate). None of the seronegative samples was positive by real-time PCR, resulting in 100% specificity. Sixteen out of 39 patients were positive by real-time PCR (41%). Concordance of results with the N-PCR was 90%. In conclusion, real-time PCR provides an optimal alternative to N-PCR, with similar sensitivity and higher throughput, and could help determine ongoing parasitaemia in chagasic patients.
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              Oral transmission of Chagas disease.

              Chagas disease is now an active disease in the urban centers of countries of nonendemicity and endemicity because of congenital and blood and/or organ transplantation transmissions and the reactivation of the chronic disease in smaller scale than vectorial transmission, reported as controlled in countries of endemicity. Oral transmission of Chagas disease has emerged in unpredictable situations in the Amazon region and, more rarely, in areas of nonendemicity where the domiciliary triatomine cycle was under control because of exposition of the food to infected triatomine and contaminated secretions of reservoir hosts. Oral transmission of Chagas disease is considered when >1 acute case of febrile disease without other causes is linked to a suspected food and should be confirmed by the presence of the parasite after direct microscopic examination of the blood or other biological fluid sample from the patient.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                26 April 2019
                2019
                : 10
                Affiliations
                1Grupo Inmunobiología y Biología Celular, Facultad de Ciencias, Pontificia Universidad Javeriana , Bogotá, Colombia
                2Grupo de Enfermedades Infecciosas, Facultad de Ciencias, Pontificia Universidad Javeriana , Bogotá, Colombia
                3Grupo de Ciencias Básicas Médicas, Facultad de Medicina, Universidad de los Andes , Bogotá, Colombia
                Author notes

                Edited by: Celio Geraldo Freire-de-Lima, Federal University of Rio de Janeiro, Brazil

                Reviewed by: Uwe Müller, Leipzig University, Germany; Christoph Hölscher, Forschungszentrum Borstel (LG), Germany

                *Correspondence: Adriana Cuéllar acuellar@ 123456javeriana.edu.co

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2019.00918
                6499084
                Copyright © 2019 Mateus, Guerrero, Lasso, Cuervo, González, Puerta and Cuéllar.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 95, Pages: 17, Words: 12150
                Funding
                Funded by: Departamento Administrativo de Ciencia, Tecnología e Innovación 10.13039/100007637
                Award ID: code: 120365842534
                Award ID: contract no. FP44842-615-2014
                Funded by: Pontificia Universidad Javeriana 10.13039/501100009543
                Award ID: proposal ID 6233
                Award ID: proposal ID 7677
                Categories
                Immunology
                Original Research

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