Abstract
Chagas disease is a life-threatening disorder caused by the protozoan parasite Trypanosoma cruzi. Parasite-specific antibodies, CD8+ T cells, as well as IFN-γ and nitric oxide (NO) are key elements of the adaptive and innate immunity against the extracellular and intracellular forms of the parasite. Bim is a potent pro-apoptotic member of the Bcl-2 family implicated in different aspects of the immune regulation, such as negative selection of self-reactive thymocytes and elimination of antigen-specific T cells at the end of an immune response. Interestingly, the role of Bim during infections remains largely unidentified. To explore the role of Bim in Chagas disease, we infected WT, Bim+/−, Bim−/− mice with trypomastigotes forms of the Y strain of T. cruzi. Strikingly, our data revealed that Bim−/− mice exhibit a delay in the development of parasitemia followed by a deficiency in the control of parasite load in the bloodstream and a decreased survival compared to WT and Bim+/− mice. At the peak of parasitemia, peritoneal macrophages of Bim−/− mice exhibit decreased NO production, which correlated with a decrease in the pro-inflammatory Small Peritoneal Macrophage (SPM) subset. A similar reduction in NO secretion, as well as in the pro-inflammatory cytokines IFN-γ and IL-6, was also observed in Bim−/− splenocytes. Moreover, an impaired anti-T. cruzi CD8+ T-cell response was found in Bim−/− mice at this time point. Taken together, our results suggest that these alterations may contribute to the establishment of a delayed yet enlarged parasitic load observed at day 9 after infection of Bim−/− mice and place Bim as an important protein in the control of T. cruzi infections.
Highlights
Trypanosoma cruzi is the etiological agent of Chagas disease, a relevant problem of global health
Splenocytes of Bim−/− mice have a deficiency in the production of nitric oxide (NO), IFN-γ, and IL-6 in the acute phase of T. cruzi infection To investigate whether the deficient response observed in T. cruziinfected Bim−/− mice was restricted to the peritoneal cavity or RESULTS Bim−/− mice are susceptible to T. cruzi infection To investigate the role of Bim during T. cruzi infection, we first analyzed the kinetics of parasitemia in WT, Bim+/−, and Bim−/− mice inoculated as described above
C, splenocytes from Bim−/− mice showed impaired release of IFN-γ and IL-6. These results suggest that the deficiency in effector function of Bim−/− immune cells after 9 days of infection with T. cruzi were not restricted to the peritoneal cavity
Summary
Trypanosoma cruzi is the etiological agent of Chagas disease, a relevant problem of global health. Along its life cycle in the insect vector and in the mammalian host, T. cruzi develops complex morphological changes that allow its replication and survival in different environmental conditions In mammals, these forms include the intracellular amastigotes—a replicative form of the parasite, and the extracellular trypomastigotes present in the blood and tissues [3]. That renders macrophages susceptible to virulent strains of Mycobacterium tuberculosis thereby promoting apoptosis of infected cells and consequent spread of the bacteria [19]. In contrast to these studies, we found that Bim is a rather positive regulator of immunity to T. cruzi. Of this molecule in the control of T. cruzi experimental infection
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