Trypanosoma cruzi Cysteine Proteases, Acting at the Interface Between the Vascular and Immune Systems, Influence Pathogenic Outcome in Experimental Chagas Disease

Abstract

Trypanosoma cruzi proteases were object of intensive structural and functional characterization in the past decades. The celebration of the Chagas disease centenarian makes it opportune to review the foundations of molecular research on cruzipain, a major lysosomal cysteine protease. Acting as a virulence factor, cruzipain promotes intracellular parasitism. In addition, tissue culture trypomastigotes (TCTs) exploit the enzymatic versatility of cruzipain to liberate kinin peptides from kininogen molecules associated to heparan sulfate proteoglycans. Acting as paracrine agonists, the released kinins (eg, lysyl-bradykinin) potentiate parasite invasion of cardiovascular cells through the signaling of heterotrimeric G-protein coupled bradykinin receptors (BKRs). Generation of kinins also stimulates immunity, implying that cruzipain activity brings mutual benefits for the host-parasite relationship. Analysis of the dynamics of inflammation revealed that TCTs induce secretion of KC/MIP-2 by macrophages via signaling of Toll-like 2 receptors (TLR2). Acting on proximal microvascular beds, CXC chemokines evoke plasma extravasations by activating endothelium/neutrophils via CXCR2. Diffusion of plasma proteins (including kininogens) through extracellular matrices allow for cruzipain-dependent generation of vasoactive kinins, which then intensify interstitial edema through the activation of endothelial BK₂R. Extent of edematogenic inflammation is counter-regulated by angiotensin converting enzyme (ACE), a kinin-degrading metallopeptidase. Acting at the interface between the vascular and the immune systems, kinins activate BK_R of dendritic cells, which then migrate to T- cell rich areas of secondary lymphoid tissues, where they induce immunoprotective type-1 effector T cells. Insight into the mechanisms regulating proteolysis in extravascular sites of infection may help to identify susceptibility markers of chronic heart disease.