title: Polyamine depletion inhibits the autophagic response modulating Trypanosoma cruzi infectivity.
abstract: Autophagy is a cell process that in normal conditions serves to recycle cytoplasmic components and aged or damaged organelles. The autophagic pathway has been implicated in many physiological and pathological situations, even during the course of infection by intracellular pathogens. Many compounds are currently used to positively or negatively modulate the autophagic response. Recently it was demonstrated that the polyamine spermidine is a physiological inducer of autophagy in eukaryotic cells. We have previously shown that the etiological agent of Chagas disease, the protozoan parasite Trypanosoma cruzi, interacts with autophagic compartments during host cell invasion and that preactivation of autophagy significantly increases host cell colonization by this parasite. In the present report we have analyzed the effect of polyamine depletion on the autophagic response of the host cell and on T. cruzi infectivity. Our data showed that depleting intracellular polyamines by inhibiting the biosynthetic enzyme ornithine decarboxylase with difluoromethylornithine (DFMO) suppressed the induction of autophagy in response to starvation or rapamycin treatment in two cell lines. This effect was associated with a decrease in the levels of LC3 and ATG5, two proteins required for autophagosome formation. As a consequence of inhibiting host cell autophagy, DFMO impaired T. cruzi colonization, indicating that polyamines and autophagy facilitate parasite infection. Thus, our results point to DFMO as a novel autophagy inhibitor. While other autophagy inhibitors such as wortmannin and 3-methyladenine are nonspecific and potentially toxic, DFMO is an FDA-approved drug that may have value in limiting autophagy and the spread of the infection in Chagas disease and possibly other pathological settings.
authors.affiliation: Laboratorio de Biología Celular y Molecular; Instituto de Histología y Embriología (IHEM); Universidad Nacional de Cuyo; CONICET; Mendoza, Argentina.
authors.forename: María C
authors.initials: MC
authors.lastname: Vanrell
authors.forename: Juan A
authors.initials: JA
authors.lastname: Cueto
authors.forename: Jeremías J
authors.initials: JJ
authors.lastname: Barclay
authors.forename: Carolina
authors.initials: C
authors.lastname: Carrillo
authors.forename: María I
authors.initials: MI
authors.lastname: Colombo
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Gottlieb
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Romano
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000518:Eflornithine / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology*; D013095:Spermidine / Q000494:pharmacology; D013997:Time Factors; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000472:pathogenicity*
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D011073:Polyamines; D013095:Spermidine; D000518:Eflornithine
keywords: ATG5; DFMO; LC3; Trypanosoma cruzi; autophagic response; autophagy; polyamines; spermidine