AUTHOR=Scharfstein Julio , Andrade Daniele , Svensjö Erik , Oliveira Ana Carolina , Nascimento Clarissa R.

TITLE=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

JOURNAL=Frontiers in Immunology

VOLUME=3

YEAR=2013

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2012.00396

DOI=10.3389/fimmu.2012.00396

ISSN=1664-3224

ABSTRACT=<p>Chronic chagasic myocarditis (CCM) depends on <italic>Trypanosoma cruzi</italic> persistence in the myocardium. Studies of the proteolytic mechanisms governing host/parasite balance in peripheral sites of <italic>T. cruzi</italic> 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 B<sub>2</sub> receptors (BK<sub>2</sub>R). 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 BK<sub>2</sub>R and ETRs, which then trigger Ca<sup>2+</sup>-driven responses that optimize the housekeeping mechanism of plasma membrane repair from cell wounding. The hypothesis predicts that the NF-κB-inducible BKR (BK<sub>1</sub>R) may integrate the multimolecular signaling platforms forged by ceramide rafts, as the chronic myocarditis progresses. Exploited as gateways for parasite invasion, BK<sub>2</sub>R, BK<sub>1</sub>R, ET<sub>A</sub>R, ET<sub>B</sub>R, and other G protein-coupled receptor partners may enable persistent myocardial parasitism in the edematous tissues at expense of adverse cardiac remodeling.</p>