Trypanosoma cruzi trypomastigotes rely on the structural diversity of the
cruzipain family of
cysteine proteases to infect and multiply in nonprofessional phagocytic cells. Herein, we will review studies demonstrating that the interplay of
cruzipain with
peptidase inhibitors modulate
infection outcome in a variety of experimental settings. Studies with a panel of T. cruzi strains showed that parasite ability to invade human smooth muscle cells is influenced by the balance between
cruzipain and chagasin, a tight binding endogenous inhibitor of
papain-like
cysteine proteases. Analysis of T. cruzi interaction with endothelial cells and cardiomyocytes indicated that parasite-induced activation of
bradykinin receptors drive host cell invasion by [Ca2+]I-dependent pathways. Clues about the mechanisms underlying
kinin generation in vivo by trypomastigotes came from analysis of the dynamics of edematogenic
inflammation. Owing to plasma extravasation, the blood-borne
kininogens accumulate in peripheral sites of
infection. Upon diffusion in peripheral tissues,
kininogens (i.e.,
type III cystatins) bind to heparan sulphate chains, thus constraining interactions of the
cystatin-like inhibitory domains with
cruzipain. The cell bound
kininogens are then turned into facile substrates for
cruzipain, which liberates
kinins in peripheral tissues. Subjected to tight-regulation by
kinin-degrading
metallopeptidases, such as
angiotensin converting enzyme, the short-lived
kinin peptides play a dual role in the host-parasite balance. Rather than unilaterally stimulating pathogen infectivity via
bradykinin receptors, the released
kinins potently induce dendritic cell maturation, thus stimulating type 1 immune responses. In conclusion, the studies reviewed herein illustrate how regulation of parasite
proteases may affect host-parasite equilibrium in the course of IT cruzi
infection.