Impact of IFN-γ Deficiency on the Cardiomyocyte Function in the First Stage of Experimental Chagas Disease

Abstract

Chagas disease (CD) is caused by the parasitic protozoan T. cruzi. The progression of CD in ~30% of patients results in Chagasic Cardiomyopathy (CCM). Currently, it is known that the inflammatory system plays a significant role in the CCM. Interferon-gamma (IFN-γ) is the major cytokine involved in parasitemia control but has also been linked to CCM. The L-type calcium current (ICa,L) is crucial in the excitation/contraction coupling in cardiomyocytes. Thus, we compared ICa,L and the mechanical properties of cardiomyocytes isolated from infected wild type (WT) and IFN-γ(−/−) mice in the first stage of T. cruzi infection. Using the patch clamp technique, we demonstrated that the infection attenuated ICa,L in isolated cardiomyocytes from the right and left ventricles of WT mice at 15 days post-infection (dpi), which was not observed in the IFN-γ(−/−) cardiomyocytes. However, ICa,L was attenuated between 26 and 30 dpi in both experimental groups. Interestingly, the same profile was observed in the context of the mechanical properties of isolated cardiomyocytes from both experimental groups. Simultaneously, we tracked the mortality and MCP-1, TNF-α, IL-12, IL-6, and IL-10 serum levels in the infected groups. Importantly, the IFN-γ(−/−) and WT mice presented similar parasitemia and serum inflammatory markers at 10 dpi, indicating that the modifications in the cardiomyocyte functions observed at 15 dpi were directly associated with IFN-γ(−/−) deficiency. Thus, we showed that IFN-γ plays a crucial role in the electromechanical remodeling of cardiomyocytes during experimental T. cruzi infection in mice.

Arrhythmogenic Manifestations of Chagas Disease: Perspectives From the Bench to Bedside

“…30 The reduction of I to and I k in T. cruzi infection, which results in the prolongation of AP duration, involves a complex interplay of several key mechanisms and was observed in the setting of intense inflammatory infiltrates affecting the heart, in both dog and mice models of T. cruzi induced myocarditis. 28,31–39…”

“…30 The reduction of I to and I k in T. cruzi infection, which results in the prolongation of AP duration, involves a complex interplay of several key mechanisms and was observed in the setting of intense inflammatory infiltrates affecting the heart, in both dog and mice models of T. cruzi induced myocarditis. 28,[31][32][33][34][35][36][37][38][39] The neurohormonal activation, particularly alterations in the adrenergic pathway influenced by factors such as noradrenaline production, plays a significant role in modulating these potassium currents, especially I to . Moreover, the infection-induced immune response leads to heightened oxidative stress and increased production of NO and ROS within the heart tissue.…”