Trypanosoma cruzi autophagy is a novel target to control parasite replication and host cell infection.

NOVICK PAUL; CLOS JOACHIM; RIVERO CYNTHIA VANESA; ROMANO PATRICIA SILVIA

(VIRTUAL)

Simposio; 1st Annual Symposium for Women in Autophagy ? Beth?s Levine Legacy Network; 2020

Women in Autophagy (WIA)

Trypanosoma cruzi is the causative agent of Chagas disease (CD), one of the most widespread neglected tropical disease in the world. Due to the two only approved drugs for CD treatment, Benznidazole and Nifurtimox, display high toxicity and low effectiveness in the chronic stage, there is an urgent necessity to find more effective treatments for this disease. Cruzipain is a cysteine protease of T. cruzi that plays a key role in parasite nutrition, differentiation and host cell infection, being considered as a validated target for new anti-parasitic drugs. Previous data from our laboratory showed that T. cruzi autophagy controls cruzipain activity during parasite differentiation and host cell infection by trypomastigotes, the infective form of T. cruzi. In this work we analyzed the action of carvedilol (CVL), a beta-blocker drug that was selected in a virtual screening for cruzipain inhibitors. We found that CVL treatment produced the accumulation of enlarged autophagy vacuoles characterized by reduced acidity and hydrolytic activity, usually observed during the autophagy flux inhibition. Interestingly, CVL treatment affected the replication of both extracellular and intracellular parasitic forms of T. cruzi and significantly reduced the parasite load in infected cells. Inhibition of autophagy by CVL also affected the infective capacity of trypomastigotes and decreased its survival. In summary, we repositioned CVL as a novel inhibitor of autophagy flux in T. cruzi that exhibits a significant anti-parasitic activity. Furthermore, we propose T. cruzi autophagy as a new target against this parasite and its inhibitors as attractive candidates for Chagas disease treatment.