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

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.

Endothelin-1 and its role in the pathogenesis of infectious diseases

“…In addition, these endothelin receptor antagonists reduced plasma leakage in the hamster cheek pouch and inhibited the inflammatory edema in T. cruzi -infected mice. These studies indicate that endothelin and bradykinin receptors-induced inflammatory cascade are triggered via TLR2/CXCR2 through the proteolytic activation of the kallikrein-kinin-system [190]. Taken together, these studies, demonstrate that the inflammatory cascade pathways that participate in cardiovascular remodeling during T. cruzi infection are both complex and interactive.…”

Reversible Cysteine Protease Inhibitors Show Promise for a Chagas Disease Cure

“…Based on the IC 50 s observed in the whole-cell assays, these levels are too low for direct antiparasitic activity. While a slow killing mechanism may be possible at these lower concentrations due to impairment of the parasite (20,50), one could also invoke mechanisms of action that are only possible in vivo, such as inhibition of direct tissue and macrophage invasion (49,51), reduction of parasite-evoked inflammatory edema that may enable persistent parasitism (52,53,54), and abrogation of host immune evasion (55,56). These biological effects are believed to be the result of cruzipain, which is tethered, secreted, or present in secluded sites of the host-parasite interface (16,17,19,28,51,53) and would be readily accessible to cruzipain inhibitors in the blood compartment.…”

Pharmacological Activities and Hydrolysis by Peptidases of [Phospho-Ser6]-Bradykinin (pS6-BK)

“…Phosphorylation of kininogens can occur and be regulated depending on the organism requirements in all tissues that generate kininogens, as in liver for HK and in all other tissues for LK. It is reasonable to conceive of the phosphorylation of the kininogens as an efficient kallikrein-kinin system regulator and functioning as a protecting mechanism in inflammatory events, as a possible route for blood pressure control and even modulating the kinin roles in immune response and neuronal function, in which the kallikrein-kinin system is involved [56,57]. Finally, the phosphorylation of kininogens can interfere in their several functionalities reviewed in [58].…”