https://doi.org/10.1007/s00392-025-02625-4
1Heidelberg University, Medical Faculty Heidelberg Institute of Experimental Cardiology Heidelberg, Deutschland; 2Bernhard Nocht Institute for Tropical Medicine Protozoa Immunology Hamburg, Deutschland; 3Universitätsklinikum Heidelberg Molekulare Kardiologie und Epigenetik Heidelberg, Deutschland; 4Universitätsklinikum Heidelberg Institut für experimentelle Kardiologie Heidelberg, Deutschland
Background: Chagas disease, caused by Trypanosoma cruzi (T. cruzi), results in chronic cardiac and gastrointestinal complications. Chagas disease vectors, triatomine insects (or Kissing bugs), stemmed originally from Americas, may extend beyond this continent due to climate factors and migration. Treatment options are limited, especially in the chronic phase. CaMKII has emerged as a promising target for small molecules to treat heart disease. We research CaMKII signaling role in Chagas cardiomyopathy using human pluripotent stem cells derived cardiomyocytes (hiPS-CM) and in vivo models.
Methods: For in vitro studies, hiPS-CM were infected with T. cruzi trypomastigotes (3:1 ratio) for 24 hours. For in vivo studies, C57BL/6J mice were infected with T. cruzi trypomastigotes at a dose of 2 x 103 trypomastigotes. Non-infected controls received PBS only. All cells and mice were infected under BSL-3 conditions (Bernhardt Nocht Institute, Hamburg).
Results: hiPS-CM were infected after 24 hours of incubation with T. cruzi. The hearts of mice did not show neither a decrease in cardiac function after 24 months of T. cruzi infection, nor an increase in hypertrophy markers. However, genes related to inflammation (TNF-alpha, IFN-gamma, and IL-6) were upregulated in the hearts of the mice. Although the mRNA of the two main isoforms of CaMKII in the heart (delta and gamma) were downregulated, the protein and phosphorylation of CaMKII were upregulated in long-term infection.
Discussion: The results suggest that T. cruzi activates CaMKII but does not induce cardiac dysfunction in C57BL6/J mice Different mouse strains (e.g. Balb/c) have been shown to develop cardiac dysfunction in response to T.cruzi infections and will be tested in the future in combination with CaMKII inhibition. Furthermore, we are developing in vitro models to understand why the obligatory intracellular parasite T. cruzi triggers an immune response from the cardiomyocyte. To do this, we will conduct proteomic studies to investigate how the parasite interacts at the intracellular level and activates CaMKII.