Resveratrol modulates Trypanosoma cruzi autophagy in a stage-specific manner reducing parasite infection.

CAMPO VANINA A

BUENOS AIRES

Congreso; DRUG DISCOVERY FOR NEGLECTED DISEASES INTERNATIONAL CONGRESS 2018; 2018

Chagas disease (or American trypanosomiasis), caused by Trypanosoma cruziinfection in humans, is considered one of the most important neglected diseases in LatinAmerica. The drugs presently used for treatment, Benznidazol and Nifurtinox, have shownlimited efficiency due to the appearance of resistant parasites and the severe side effects.Thus, there is a clear need for development of new therapeutic alternatives. Focusing onregulatory processes essential for parasite growth and development, such as proteinacetylation [1-3] represents a promising starting point for identifying new anti-parasitic drugs.Protein acetylation is a reversible reaction modulated by Acetyl Transferases (KATs) andDeacetylases (KDACs) enzymes. As a result, these enzymes are involved in regulating importantcellular processes covering from chromatin structure and gene expression to metabolic state.KDACs have been intensively studied as drug targets in humans, and the anti-parasitic effectsof different compound modulators of parasite KDACs activity have been reported [1-8]. It wasrecently reported that resveratrol (RSV), a situins deacetylases activator, reduced T. cruzi CLBrener epimastigotes growth and cell-derived trypomastigotes infectivity [8]; in accordancewith previous reports describing the anti-parasite effects of RSV on Leishmania major [9] andother T. cruzi strains [10]. It is also described, that pre activation of the host cells autophagicpathway facilitates T. cruzi infection [11]. Since resveratrol is now widely used in humans andhas been shown to be completely non-toxic [12], it became a very attractive candidate as arepositioning drug. In this context, the present study describes the effect of this compound asa modulator of both parasite and host cell autophagy as one of the main mechanismsresponsible of its anti-parasite activity. Real time PCR (qPCR) analysis of autophagic keyproteins ATG3, ATG7 and ATG8 and western blot analysis of LC3B I and II ratio changes showedthat parasites treatment with RSV cause stage-specific effects, promoting epimastigoteautophagy while blocking this process in infective trypomastigotes. Moreover, in vitro infectionassays using two different types (Vero and L929) of host cells pre-treated with RSV reducedparasite infection by 50%. These two cell lines showed different sensibility to RSV showing inboth cases inhibition of autophagy in a concentration dependent manner according to analysisof autophagic indicators using immunofluorescence, western blot, qPCR andmonodansylcadaverine staining.