IL-33/ST2 Signaling Protects the Heart by Restraining Inflammation and Parasite Burden during <i>Trypanosoma cruzi</i> Experimental Infection

Abstract

Chagas disease (CD), caused by the parasite <i>Trypanosoma cruzi</i>, 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 <i>T. cruzi</i>-induced myocarditis remains unclear. Here, using ST2-deficient (ST2^-/-) and wild-type (WT) female mice infected with the <i>T. cruzi</i> 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 <i>T. cruzi</i> experimental infection. Targeting this pathway may offer therapeutic potential for preventing cardiac damage in CD.

Affiliated Institutions

• Institut des Sciences Biologiques FR
• Infectious Diseases Institute UG
• Universidade Federal de Minas Gerais BR

Related Publications