Absence of Bim sensitizes mice to experimental Trypanosoma cruzi infection

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.

Balancing life and death: BCL‐2 family members at diverse ER–mitochondrial contact sites

“…Another setting may be pathogen infection, which triggers BAX/BAK activation in a limited number of mitochondria, so-called minority MOMP, to induce STING without caspase activation [439]. Interestingly, loss of BIM prevents pro-inflammatory cytokine production in response to T. cruzi infection in vivo, and induction of PUMA has also been shown to promote cytosolic release of mitochondrial DNA and activation of STING [440,441]. This raises the question of whether BH3-only proteins are also involved in mitochondrial DNA release and STING stimulation through BAX/BAK and MAMs or if they are acting through a separate pathway.…”

Immunopathogenesis in Trypanosoma cruzi infection: a role for suppressed macrophages and apoptotic cells

“…Moreover, these studies revealed that caspase-8 is also required for CD8 T cell expansion during T. cruzi infection ( 60 ). Finally, Bim-deleted mice are more susceptible to T. cruzi infection, most likely owing to defective macrophage and T cell responses ( 68 ). Therefore, the translation of apoptosis inhibition into treatment for chronic diseases is unlikely so far.…”