IL-33/ST2 Signaling Protects the Heart by Restraining Inflammation and Parasite Burden during Trypanosoma cruzi Experimental Infection
Related Experiment Video
Updated: Jan 9, 2026
Quantitative 3D Imaging of Trypanosoma cruzi-Infected Cells, Dormant Amastigotes, and T Cells in Intact Clarified Organs
Published on: June 23, 2022
Marcelo Eduardo Cardozo1,2, Tatyane Martins Cirilo1, Jorge Lucas Nascimento Souza1
1Laboratory of Immunobiology and Parasite Control, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.
Insights
The Interleukin-33 (IL-33)/ST2 pathway protects against Chagas disease (CD) heart damage by limiting inflammation and immune dysfunction. Its absence worsens myocarditis and parasite control in experimental infections.
Area of Science:
- Immunology
- Parasitology
- Cardiology
Background:
- Chagas disease (CD), caused by *Trypanosoma cruzi*, leads to severe cardiac damage.
- The immune system's role in CD pathogenesis is complex, influencing host protection and parasite persistence.
- Interleukin-33 (IL-33) and its receptor ST2 are involved in tissue injury responses, but their role in *T. cruzi*-induced myocarditis is unknown.
Purpose of the Study:
- To investigate the contribution of the IL-33/ST2 axis to cardiac inflammation, tissue damage, and parasite burden in experimental Chagas disease.
- To elucidate the impact of ST2 deficiency on the cardiac immune landscape and host response to *T. cruzi* infection.
Main Methods:
- Comparison of ST2-deficient (ST2-/-) and wild-type (WT) female mice infected with the *T. cruzi* Y strain.
- Assessment of cardiac inflammation, fibrosis, electrical conduction, parasite burden, and immune cell profiles (monocytes, macrophages, T cells).
- Analysis of cytokine production, including Interferon-gamma (IFN-γ) and nitric oxide.
Main Results:
- ST2 signaling was not critical for controlling parasitemia but its absence accelerated myocarditis and disorganized cardiac fibrosis.
- ST2 deficiency resulted in an influx of IFN-γ-producing monocytes and pro-inflammatory macrophages.
- Cardiac T cell populations shifted towards an inflammatory, IFN-γ-driven profile in ST2-/- mice.
- ST2-deficient mice showed increased cardiac parasite burden and impaired nitric oxide production.
Conclusions:
- The IL-33/ST2 axis plays a protective role by limiting early systemic inflammation and orchestrating the cardiac immune response during *T. cruzi* infection.
- ST2 signaling is crucial for preventing severe immunopathology, cardiac fibrosis, and electrical remodeling in experimental Chagas disease.
- Targeting the IL-33/ST2 pathway holds therapeutic potential for mitigating cardiac damage in Chagas disease.
Abstract:
Chagas disease (CD), caused by the parasite Trypanosoma cruzi, affects millions of people worldwide and often leads to fatal heart damage. The course of CD is influenced by how the immune system is tuned, which can protect the host and favor parasite persistence. Interleukin-33 (IL-33) is an alarmin released upon tissue injury that signals through the ST2 receptor, exerting context-dependent regulatory or pathogenic effects. However, the role of the IL-33/ST2 axis in T. cruzi-induced myocarditis remains unclear. Here, using ST2-deficient (ST2-/-) and wild-type (WT) female mice infected with the T. cruzi Y strain, we investigated its contribution to cardiac inflammation, tissue damage, and parasite burden. We found that ST2 signaling was not essential for controlling parasitemia, but its deficiency led to early onset myocarditis, disorganized fibrosis, and distinct electrical conduction. This severe immunopathology was driven by a remodeling of the cardiac immune landscape, with ST2-/- mice exhibiting an influx of IFN-γ-producing monocytes and a shift in resident and monocyte-derived macrophages toward a pathogenic, pro-inflammatory phenotype. Likewise, the cardiac T cell compartment, including both conventional and γδ T cells, was skewed toward an inflammatory, IFN-γ-driven profile. However, infected ST2-deficient mice also displayed higher cardiac parasite burden and impaired nitric oxide production, indicating a dysfunctional response in parasite control. Together, these findings demonstrate that the IL-33/ST2 axis limits early systemic inflammation, orchestrates cardiac immune response, and protects against immunopathology and electrical remodeling during T. cruzi experimental infection. Targeting this pathway may offer therapeutic potential for preventing cardiac damage in CD.
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