**Abstract**

Enzymes called proteases play important roles in the physiology of all living organisms and in the interaction of a parasite/symbiont with its host. Different types of peptidases act on specific substrates and are regulated by specific inhibitors. Ecotins, described firstly in *Eschericchia coli*, are inhibitors of serine peptidases (ISP) from S1A family including trypsin, chymotrypsin, neutrophil elastase, and cathepsin G. Ecotin-like inhibitors are present in parasites from Trypanosomatidae family, including *Trypanosoma cruzi*, the causative agent of Chagas' disease. This chapter explores the evolutive origin of the *T. cruzi* TcISP2 and its possible interactions with proteins of the human immune system and in Chagas' disease. The phylogenetic relationship of TcISP2 with trypanosomatids ISPs, comparative loci analysis among trypanosomatids, and the occurrence of bacteria endosymbionts in the group strongly suggest horizontal transfer as the main origin mechanism for trypanosomatids ISPs, followed by duplication events and losses that could explain its current genomic pattern. The relationship of TcISP2 with the vertebrate host immune system can be inferred by its antigenicity in Chaga's disease murine model, presenting high antibody titer after 60 days post-infection, which could indicate the inhibition of TcISP2 activity associated with chronic phase of the Chaga's disease.

**Keywords:** *Trypanosoma cruzi*, ecotin, serine-protease inhibitor, recombinant protein, neutrophil elastase
