Abstract
Trypanosoma cruzi proteases were object of intensive structural and functional characterization in the past de- cades. The celebration of the Chagas disease centenarian makes it opportune to review the foundations of molecular re- search 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 re- leased kinins (eg, lysyl-bradykinin) potentiate parasite invasion of cardiovascular cells through the signaling of hetero- trimeric 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 re- vealed 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 metal- lopeptidase. Acting at the interface between the vascular and the immune systems, kinins activate BK2R of dendritic cells, which then migrate to T- cell rich areas of secondary lymphoid tissues, where they induce immunoprotective type-1 effec- tor T cells. Insight into the mechanisms regulating proteolysis in extravascular sites of infection may help to identify sus- ceptibility markers of chronic heart disease.
Highlights
After decades of research, a large body of studies in humans [1,2,3,4] and animal models [5] indicate that lowgrade/persistent tissue parasitism is the primary mechanism underlying chronic chagasic myocardiopathy (CCM)
The results from this study showed that chagasin overexpression impairs biological functions that are typically linked to cruzipain activity, such as ability to invade myofibroblasts in culture systems [100]
The kinin peptides have been traditionally viewed as classical mediators of acute inflammation, we have recently demonstrated that bradykinin is an endogenous danger signal that steers TH1 polarization through the activation of conventional CD11c+dendritic cell (DC) [115]
Summary
A large body of studies in humans [1,2,3,4] and animal models [5] indicate that lowgrade/persistent tissue parasitism is the primary mechanism underlying chronic chagasic myocardiopathy (CCM). Chronic infection does not lead to clinically active heart disease, implying that anti-parasite effector T cells may succeed at controlling intracellular parasite outgrowth in the myocardium without necessarily causing collateral damage. Inflammation scores were similar in all groups of infected mice, whereas chronic fibrosis was reduced in ET- 1 flox/flox ;-MHC-Cre (+) mice. They noted a significant increase in the right ventricular internal diameter (RVID) of all infected mice, except for the ET-1 flox/flox ;-MHC-Cre (+) mice strain. Pooling results from magnetic resonance imaging and echocardiography, these authors proposed that clinical outcome of CCM may be worsened as result of ET-1 upregulation by cardiac myocytes [20]
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