Roles of naturally occurring protease inhibitors in the modulation of host cell signaling and cellular invasion by Trypanosoma cruzi.
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.
Lnstituto de Biofisica Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brazil. scharf@biof.ufrj.br
Julio
J
Scharfstein
Ana Paula C A
AP
Lima
D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006790:Host-Parasite Interactions; D006801:Humans; D008954:Models, Biological; D011480:Protease Inhibitors / Q000378:metabolism*; D015800:Protozoan Proteins; D015398:Signal Transduction; D014349:Trypanosoma cruzi / Q000378:metabolism* / Q000472:pathogenicity*
D011480:Protease Inhibitors; D015800:Protozoan Proteins; D003546:Cysteine Endopeptidases; C063214:cruzipain