Difluoromethylornithine (DFMO) is a new inhibitor of Autophagy and Trypanosoma cruzi infection.?

VANRELL MC; CUETO JA; BARCLAY JJ; COLOMBO MI; CARRILLO C; GOTTLIEB RA; ROMANO PS

Congreso; SAIB XLVIII Reunion anual; 2012

DIFLUOROMETHYLORNITHINE (DFMO) IS A NEW INHIBITOR OF AUTOPHAGY AND INFECTION Trypanosoma cruzi 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. Recently it was demonstrated that the polyamine spermidine is a physiological inducer of autophagy. Otherwise, autophagy induction significantly increases host cell colonization by , the etiological agent of Chagas disease. In this work we have analyzed the effect of polyamine depletion on the autophagic response of the host cell and on infectivity. Our data show that depleting intracellular polyamines by inhibiting the biosynthetic enzyme ornithine decarboxylase with DFMO suppressed the induction of autophagy associated with a decrease in protein abundance of LC3 and Atg5, two proteins required for autophagosome formation. As a consequence of inhibiting host cell autophagy, DFMO impaired colonization, indicating that polyamines and autophagy facilitate parasite infection. While other autophagy inhibitors are nonspecific and potentially toxic, DFMO is an FDA approved drug that may have value in limiting autophagy and spread of the infection in Chagas disease and possibly other pathological settings. Vanrell MC , Cueto JA , Barclay JJ , Colombo MI , Carillo C , Gottlieb RA , . IHEM-CONICET. FCM. UNCuyo, Mza. ICT Milstein-CONICET, Bs. As. SDSU Bioscience Center, San Diego E-mail: promano@fcm.uncu.edu.ar