Related Experiment Video
Updated: Sep 17, 2025
Quantitative 3D Imaging of Trypanosoma cruzi-Infected Cells, Dormant Amastigotes, and T Cells in Intact Clarified Organs
Published on: June 23, 2022
Purinergic signaling modulates CD4+ T cells with cytotoxic potential during Trypanosoma cruzi infection
Gastón Bergero1,2,3, Yanina L Mazzocco1,2, Sebastian Del Rosso1,2
1Universidad Nacional de Córdoba, Facultad de Ciencias Químicas, Departamento de Bioquímica Clínica, Córdoba, Argentina.
Insights
Hypoxia stabilizes HIF-1 in Chagas disease, promoting immunosuppressive adenosine via CD39/CD73 on CD4+ T cells. This impairs T cell killing, aiding parasite persistence and chronic inflammation.
Area of Science:
- Immunology
- Parasitology
- Molecular Biology
Background:
- Chagas disease, caused by Trypanosoma cruzi, leads to chronic cardiac inflammation and parasite persistence.
- Tissue hypoxia in infected areas may stabilize Hypoxia-Inducible Factor 1 (HIF-1) and influence ATP metabolism.
- Extracellular adenosine (ADO), generated by CD39 and CD73 ectonucleotidases from ATP, acts as a potent immunosuppressor.
Purpose of the Study:
- To investigate the role of HIF-1 stabilization and the CD39/CD73/ADO axis in CD4+ T cells during Trypanosoma cruzi infection.
- To understand how these pathways contribute to parasite persistence and chronic inflammation in Chagas disease.
Main Methods:
- Analysis of myocardial tissue from infected models and patients with end-stage Chagas disease.
- Assessment of HIF-1α stabilization in T cells within hypoxic cardiac tissues.
- Evaluation of CD39 and CD73 expression and activity on infiltrating CD4+ T cells.
- Functional assays to determine the impact of HIF-1 stabilization and CD73 activity on CD4+ T cell cytotoxicity.
- RNA-Seq analysis to identify overrepresented pathways in cardiac tissues.
Main Results:
- Myocardial infection with T. cruzi induced significant hypoxia and HIF-1α stabilization in cardiac T cells.
- Early infiltration of CD39+CD73+CD4+ T cells correlated with hypoxia.
- HIF-1 stabilization and CD73 activity were associated with reduced CD4+ T cell cytotoxic function.
- RNA-Seq data showed enrichment of HIF-1 and purinergic signaling pathways in end-stage Chagas disease cardiac tissues.
Conclusions:
- HIF-1 stabilization and the CD39/CD73/ADO pathway in CD4+ T cells play a critical role in facilitating Trypanosoma cruzi persistence.
- These findings reveal a significant impact of purinergic signaling on cytotoxic CD4+ T cells during Chagas disease.
- The study suggests potential therapeutic targets within the purinergic signaling pathway for Chagas disease treatment.
Abstract:
Chagas disease, caused by Trypanosoma cruzi, is endemic to Latin America and is characterized by chronic inflammation of cardiac tissues due to parasite persistence. Hypoxia within infected tissues may trigger the stabilization of HIF-1 and be linked to ATP release. Extracellular ATP exhibits microbicidal effects but is scavenged by CD39 and CD73 ectonucleotidases, which ultimately generate adenosine (ADO), a potent immunosuppressor. Here, we comprehensively study the importance of HIF-1 stabilization and the CD39/CD73/ADO axis, on CD4+ T cells with the cytotoxic phenotype, in facilitating the persistence of T. cruzi. Myocardial infection induces prominent areas of hypoxia, which is concomitant with HIF-1α stabilization in T cells and linked to early expansion of CD39+CD73+CD4+ T cell infiltrating population. Functional assays further demonstrate that HIF-1 stabilization and CD73 activity are associated with impaired CD4+ T cell cytotoxic potential. RNA-Seq analysis reveals that HIF-1 and purinergic signaling pathways are overrepresented in cardiac tissues of patients with end-stage Chagas disease. The findings highlight a major effect of purinergic signaling on CD4+ T cells with potential cytotoxic capacity in the setting of T. cruzi infection and have translational implications for therapy.
Related Concept Videos
01:27Cytotoxic T Cells-mediated Immune Response
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
01:24T Cell Types and Functions
Th1 cells stimulate dendritic cells to express necessary co-stimulatory molecules on their surfaces for...
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...