Abstract
Chronic chagasic myocarditis (CCM) depends on Trypanosoma cruzi persistence in the myocardium. Studies of the proteolytic mechanisms governing host/parasite balance in peripheral sites of T. cruzi infection revealed that tissue culture trypomastigotes (TCTs) elicit inflammatory edema and stimulate protective type-1 effector T cells through the activation of the kallikrein-kinin system. Molecular studies linked the proinflammatory phenotype of Dm28c TCTs to the synergistic activities of tGPI, a lipid anchor that functions as a Toll-like receptor 2 (TLR2) ligand, and cruzipain, a kinin-releasing cysteine protease. Analysis of the dynamics of inflammation revealed that TCTs activate innate sentinel cells via TLR2, releasing CXC chemokines, which in turn evoke neutrophil/CXCR2-dependent extravasation of plasma proteins, including high molecular weight kininogen (HK), in parasite-laden tissues. Further downstream, TCTs process surface bound HK, liberating lysyl-BK (LBK), which then propagates inflammatory edema via signaling of endothelial G-protein-coupled bradykinin B2 receptors (BK2R). Dm28 TCTs take advantage of the transient availability of infection-promoting peptides (e.g., bradykinin and endothelins) in inflamed tissues to invade cardiovascular cells via interdependent signaling of BKRs and endothelin receptors (ETRs). Herein we present a space-filling model whereby ceramide-enriched endocytic vesicles generated by the sphingomyelinase pathway might incorporate BK2R and ETRs, which then trigger Ca2+-driven responses that optimize the housekeeping mechanism of plasma membrane repair from cell wounding. The hypothesis predicts that the NF-κB-inducible BKR (BK1R) may integrate the multimolecular signaling platforms forged by ceramide rafts, as the chronic myocarditis progresses. Exploited as gateways for parasite invasion, BK2R, BK1R, ETAR, ETBR, and other G protein-coupled receptor partners may enable persistent myocardial parasitism in the edematous tissues at expense of adverse cardiac remodeling.
Highlights
Afflicting nearly 10 million people in Latin America (Coura and Dias, 2009), Chagas disease is a pleiomorphic clinical entity caused by Trypanosoma cruzi, a parasitic protozoan that undergoes obligate intracellular development in the mammalian host
In invasion assays performed with LPSHUVECs or cardiomyocytes, we found that ACE inhibitors were not required to promote parasite uptake via BK1R, as opposed to the ACE inhibitor-dependent phenotype displayed by resting human umbilical vein endothelial cells (HUVECs) (Todorov et al, 2003; Andrade et al, 2012)
The physical association of these G proteincoupled receptors (GPCRs) was not demonstrated at the molecular level, these results suggest that the cross-talk between endothelin receptors (ETRs) and BK2R may critically depend on the integrity of lipid rafts/caveolae (Figure 3)
Summary
Afflicting nearly 10 million people in Latin America (Coura and Dias, 2009), Chagas disease is a pleiomorphic clinical entity caused by Trypanosoma cruzi, a parasitic protozoan that undergoes obligate intracellular development in the mammalian host. Studies in various experimental models indicated that tissue culture-derived trypomastigotes (Dm28c) swiftly activate microvascular beds through the activation of the KKS (Todorov et al, 2003; Monteiro et al, 2006; Schmitz et al, 2009; Scharfstein and Andrade, 2011; Andrade et al, 2012) Based on these initial observations, we predicted that the sudden diffusion of plasma-borne constituents (antibodies, complement components, kininogens, ETs) through parasite-laden tissues may affect the delicate host/parasite balance established in the chronically infected myocardium. A growing number of studies indicated that immune resistance against infection by parasitic protozoan (Monteiro et al, 2006, 2007; Svensjö et al, 2006; Nico et al, 2012; Scharfstein and Svensjö, 2012) and bacterial pathogens
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