Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of <i>Trypanosoma cruzi</i> Infection
Chagas cardiomyopathy is caused by <i>Trypanosoma cruzi</i> (<i>Tc</i>). We identified two candidate antigens (TcG2 and TcG4) that elicit antibodies and T cell responses in naturally infected diverse hosts. In this study, we cloned <i>TcG2</i> and <i>TcG4<...
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| Format: | Article |
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MDPI AG
2020-02-01
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| Series: | Vaccines |
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| Online Access: | https://www.mdpi.com/2076-393X/8/1/96 |
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| author | Nandadeva Lokugamage Subhadip Choudhuri Carolina Davies Imran Hussain Chowdhury Nisha Jain Garg |
| author_facet | Nandadeva Lokugamage Subhadip Choudhuri Carolina Davies Imran Hussain Chowdhury Nisha Jain Garg |
| author_sort | Nandadeva Lokugamage |
| collection | DOAJ |
| description | Chagas cardiomyopathy is caused by <i>Trypanosoma cruzi</i> (<i>Tc</i>). We identified two candidate antigens (TcG2 and TcG4) that elicit antibodies and T cell responses in naturally infected diverse hosts. In this study, we cloned <i>TcG2</i> and <i>TcG4</i> in a nanovector and evaluated whether nano-immunotherapy (referred as nano2/4) offers resistance to chronic Chagas disease. For this, C57BL/6 mice were infected with <i>Tc</i> and given nano2/4 at 21 and 42 days post-infection (pi). Non-infected, infected, and infected mice treated with pcDNA3.1 expression plasmid encoding <i>TcG2/TcG4</i> (referred as p2/4) were used as controls. All mice responded to <i>Tc</i> infection with expansion and functional activation of splenic lymphocytes. Flow cytometry showed that frequency of splenic, poly-functional CD4<sup>+</sup> and CD8<sup>+</sup> T cells expressing interferon-γ, perforin, and granzyme B were increased by immunotherapy (<i>Tc.</i>nano2/4 > <i>Tc.</i>p2/4) and associated with 88%−99.7% decline in cardiac and skeletal (SK) tissue levels of parasite burden (<i>Tc.</i>nano2/4 > <i>Tc.</i>p2/4) in Chagas mice. Subsequently, <i>Tc.</i>nano2/4 mice exhibited a significant decline in peripheral and tissues levels of oxidative stress (e.g., 4-hydroxynonenal, protein carbonyls) and inflammatory infiltrate that otherwise were pronounced in Chagas mice. Further, nano2/4 therapy was effective in controlling the tissue infiltration of pro-fibrotic macrophages and established a balanced environment controlling the expression of collagens, metalloproteinases, and other markers of cardiomyopathy and improving the expression of <i>Myh7</i> (encodes β myosin heavy chain) and <i>Gsk3b</i> (encodes glycogen synthase kinase 3) required for maintaining cardiac contractility in Chagas heart. We conclude that nano2/4 enhances the systemic T cell immunity that improves the host’s ability to control chronic parasite persistence and Chagas cardiomyopathy. |
| first_indexed | 2024-04-13T06:20:21Z |
| format | Article |
| id | doaj.art-cea0a5a99f0a4018ae138eeb1e32c351 |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-04-13T06:20:21Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-cea0a5a99f0a4018ae138eeb1e32c3512022-12-22T02:58:41ZengMDPI AGVaccines2076-393X2020-02-01819610.3390/vaccines8010096vaccines8010096Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of <i>Trypanosoma cruzi</i> InfectionNandadeva Lokugamage0Subhadip Choudhuri1Carolina Davies2Imran Hussain Chowdhury3Nisha Jain Garg4Department of Microbiology and Immunology, The University of Texas Medical Branch (UTMB), Galveston, TX 77555-1070, USADepartment of Microbiology and Immunology, The University of Texas Medical Branch (UTMB), Galveston, TX 77555-1070, USAInstituto de Patología Experimental, Universidad Nacional de Salta-CONICET, Salta 4400, ArgentinaDepartment of Microbiology and Immunology, The University of Texas Medical Branch (UTMB), Galveston, TX 77555-1070, USADepartment of Microbiology and Immunology, The University of Texas Medical Branch (UTMB), Galveston, TX 77555-1070, USAChagas cardiomyopathy is caused by <i>Trypanosoma cruzi</i> (<i>Tc</i>). We identified two candidate antigens (TcG2 and TcG4) that elicit antibodies and T cell responses in naturally infected diverse hosts. In this study, we cloned <i>TcG2</i> and <i>TcG4</i> in a nanovector and evaluated whether nano-immunotherapy (referred as nano2/4) offers resistance to chronic Chagas disease. For this, C57BL/6 mice were infected with <i>Tc</i> and given nano2/4 at 21 and 42 days post-infection (pi). Non-infected, infected, and infected mice treated with pcDNA3.1 expression plasmid encoding <i>TcG2/TcG4</i> (referred as p2/4) were used as controls. All mice responded to <i>Tc</i> infection with expansion and functional activation of splenic lymphocytes. Flow cytometry showed that frequency of splenic, poly-functional CD4<sup>+</sup> and CD8<sup>+</sup> T cells expressing interferon-γ, perforin, and granzyme B were increased by immunotherapy (<i>Tc.</i>nano2/4 > <i>Tc.</i>p2/4) and associated with 88%−99.7% decline in cardiac and skeletal (SK) tissue levels of parasite burden (<i>Tc.</i>nano2/4 > <i>Tc.</i>p2/4) in Chagas mice. Subsequently, <i>Tc.</i>nano2/4 mice exhibited a significant decline in peripheral and tissues levels of oxidative stress (e.g., 4-hydroxynonenal, protein carbonyls) and inflammatory infiltrate that otherwise were pronounced in Chagas mice. Further, nano2/4 therapy was effective in controlling the tissue infiltration of pro-fibrotic macrophages and established a balanced environment controlling the expression of collagens, metalloproteinases, and other markers of cardiomyopathy and improving the expression of <i>Myh7</i> (encodes β myosin heavy chain) and <i>Gsk3b</i> (encodes glycogen synthase kinase 3) required for maintaining cardiac contractility in Chagas heart. We conclude that nano2/4 enhances the systemic T cell immunity that improves the host’s ability to control chronic parasite persistence and Chagas cardiomyopathy.https://www.mdpi.com/2076-393X/8/1/96<i>trypanosoma cruzi</i>chagas diseaseimmunotherapycardiomyopathyfibrosisoxidative stresscd8<sup>+</sup>t cells |
| spellingShingle | Nandadeva Lokugamage Subhadip Choudhuri Carolina Davies Imran Hussain Chowdhury Nisha Jain Garg Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of <i>Trypanosoma cruzi</i> Infection Vaccines <i>trypanosoma cruzi</i> chagas disease immunotherapy cardiomyopathy fibrosis oxidative stress cd8<sup>+</sup>t cells |
| title | Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of <i>Trypanosoma cruzi</i> Infection |
| title_full | Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of <i>Trypanosoma cruzi</i> Infection |
| title_fullStr | Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of <i>Trypanosoma cruzi</i> Infection |
| title_full_unstemmed | Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of <i>Trypanosoma cruzi</i> Infection |
| title_short | Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of <i>Trypanosoma cruzi</i> Infection |
| title_sort | antigen based nano immunotherapy controls parasite persistence inflammatory and oxidative stress and cardiac fibrosis the hallmarks of chronic chagas cardiomyopathy in a mouse model of i trypanosoma cruzi i infection |
| topic | <i>trypanosoma cruzi</i> chagas disease immunotherapy cardiomyopathy fibrosis oxidative stress cd8<sup>+</sup>t cells |
| url | https://www.mdpi.com/2076-393X/8/1/96 |
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