Involvement of Poly(ADP-ribose) glycohydrolase in T. cruzi proliferation and host cell infection

SALOMÉ VILCHEZ LARREA; MARIANA SCHLESINGER; MARÍA LAURA KEVORKIAN; MIRTHA M. FLAWIÁ; GUILLERMO D. ALONSO; SILVIA H. FERNÁNDEZ VILLAMIL

Puerto Varas

Congreso; XII PABMB Congress; 2013

Trypanosoma cruzi, etiological agent of Chagas´ disease, has a complex life cycle which involves the invasion of mammalian host cells, differentiation and intracellular replication. Poly(ADP-ribosyl)ation is an early cellular response to DNA damage and is a concerted and dynamic process: poly(ADP-ribose) polymerases catalyze the transfer of ADP-ribose (ADPr) to specific target proteins, whereas poly(ADP-ribose) glycohydrolase (PARG) represents the main pADPr hydrolyzing activity in the cell. Scarce information is available on the role of pADPr metabolism in T.cruzi, here we report the possible role for T.cruzi PARG in the cell cycle of these parasites. PARG inhibitors ADP-HPD or DEA (1 µM), reduce in vitro T. cruzi epimastigote growth by ~35% when compared to control cultures and lead to a delay in the progression of the cell cycle in HU synchronized cultures, particularly affecting the S phase. More importantly, we demonstrate that the lack of PARG activity in different host cells by chemical inhibition or iRNA, reduces the percentage of infected cells as well as the number of amastigotes per cell and trypomastigotes in the supernatant, leading to a nearly complete abrogation of the infection process. PARG has proven to be an important player in the life cycle of T.cruzi and has emerged as a promising potential therapeutic for the treatment of Chagas´ disease.