The kallikrein-kinin system in experimental Chagas disease: a paradigm to investigate the impact of inflammatory edema on GPCR-mediated pathways of host cell invasion by Trypanosoma cruzi

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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.

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