Autophagy plays a protective role against Trypanosoma cruzi infection in mice

Abstract

Autophagy is a catabolic pathway required for cellular and organism homeostasis. Autophagy participates in the innate and adaptive immune responses at different levels. Xenophagy is a class of selective autophagy that involves the elimination of intracellular pathogens. Trypanosoma cruzi is the causative agent of Chagas, a disease that affects 8 million individuals worldwide. Previously, our group has demonstrated that autophagy participates in the invasion of T. cruzi in non-phagocytic cells. In this work we have studied the involvement of autophagy in the development of T. cruzi infection in mice. Beclin-1 is a protein essential for autophagy, required for autophagosome biogenesis and maturation. We have performed an acute model of infection on the autophagic deficient Beclin-1 heterozygous knock-out mice (Bcln ± ) and compared to control Bcln +/+ animals. In addition, we have analyzed the infection process in both peritoneal cells and RAW macrophages. Our results have shown that the infection was more aggressive in the autophagy-deficient mice, which displayed higher numbers of parasitemia, heart´s parasitic nests and mortality rates. We have also found that peritoneal cells derived from Bcln ± animals and RAW macrophages treated with autophagy inhibitors displayed higher levels of infection compared to controls. Interestingly, free cytosolic parasites recruited LC3 protein and other markers of xenophagy in control compared to autophagy-deficient cells. Taken together, these data suggest that autophagy plays a protective role against T. cruzi infection in mice, xenophagy being one of the processes activated as part of the repertoire of immune responses generated by the host.

Rapamycin Treatment Reduces Acute Myocarditis Induced by <b><i>Trypanosoma cruzi</i></b> Infection

“…This is also observed in other cardiomyopathies, that autophagy is upregulated in connective tissue, organizing cardiac remodeling [32,33]. Besides, the evaluation of autophagy in splenocytes and cardiac T cells corroborates the higher activation of this process in T cells from infected mice, also in effector CD44 high T cells, which implies that in vivo infection is also an autophagy inducer, as recently shown by immunoblot-ting using the liver of infected animals [17,25]. As described in in vitro studies, the pathogen can induce autophagy, upregulating LC3 and other autophagy genes.…”

“…First, we evaluated if autophagy in cardiac fibers is upregulated in vivo after T. cruzi infection, as observed in the liver [17,25], and in vitro in different lineage cells by others [26,28,29]. To this end, the mice were infected and the presence of LC3 puncta was investigated by immunostaining in cardiac ventricles sections ( Fig.…”

Host‐parasite dynamics in Chagas disease from systemic to hyper‐local scales

“…The infection, cell necrosis and associated inflammatory signalling result in the activation of a range of innate effector mechanisms. There is some evidence from analysis of Beclin‐1‐deficient mice that host cell autophagy can provide some marginal early restraint on parasite replication 82 . Epimastigotes are complement‐sensitive but trypomastigotes have effective molecular mechanisms providing resistance to complement‐mediated lysis 83 .…”

Effects of Trichinella spiralis and its excretory/secretory products on autophagy of host muscle cells in vivo and in vitro

“…Numerous studies demonstrated that autophagy could be triggered during microbial infection, such as bacteria, viruses, protozoa, and parasitic helminths [ 20 – 23 ]. However, autophagy induction has not been confirmed in Trichinella infection.…”