Papel do receptor ST2 no desenvolvimento da resposta imune e patogênese na infecção experimental aguda por Trypanosoma cruzi

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects approximately 6 million people worldwide, mainly in endemic countries in Latin America. The parasite induces a robust immunopathology, frequently resulting in cardiac, hepatic, and intestinal dysfunctions. Modulation of the immune response is essential for both host and parasite survival. Interleukin-33 (IL-33) exhibits pleiotropic effects during infections, potentially acting as either protective or detrimental. IL-33 binds to the suppressor of tumorigenicity 2 (ST2) receptor, which is expressed on a variety of cells, including leukocytes. In this context, this study aimed to investigate the role of the ST2 receptor during the acute phase of experimental T. cruzi infection. For that, female BALB/c mice, wild-type (WT) and ST2 receptor genetically deficient (ST2-/-) mice, aged between 8 and 10 weeks, were infected with 1000 blood trypomastigotes of T. cruzi Y strain. Parasitological, immunological and pathophysiological evaluations were performed at distinct time points during the acute phase of infection to characterize the development of pathogenesis. The absence of ST2 was observed to result in a transient decrease in parasitemia at 7 days post-infection (dpi), accompanied by the development of early myocarditis and increased CK-MB levels. With the progression of infection (20 dpi), ST2-/- mice exhibited leukocyte accumulation in the liver and intestine, associated with functional impairment in these organs. In the heart, degenerative changes and impaired cardiac electrical function were observed. Evaluation of the immune response revealed exacerbated inflammatory responses in the spleen, with increased expression of IFN-γ and TNF-α in lymphocytes. In cardiac tissue, a reduction in the resident cardiac macrophage population was observed, alongside an increased recruitment of MHC II+ CCR2+ macrophages and monocytes. Furthermore, ST2 deficiency led to a generalized enhancement of IFN-γ expression by various cell populations, including CD4+ and CD8+ T lymphocytes, monocytes, neutrophils, and macrophages. In conclusion, the IL-33/ST2 axis plays an essential role in regulating the inflammatory response and maintaining tissue homeostasis during acute T. cruzi infection. The data obtained in this study contribute to the understanding of the immunopathological mechanisms of Chagas disease and, consequently, may guide the development of new control or therapeutic strategies.