Infection-associated vasculopathy in experimental chagas disease pathogenic roles of endothelin and kinin pathways.

Abstract

Acting at the interface between microcirculation and immunity, Trypanosoma cruzi induces modifications in peripheral tissues which translate into mutual benefits to host/parasite balance. In this chapter, we will review evidence linking infection-associated vasculopathy to the proinflammatory activity of a small subset of T. cruzi molecules, namely GPI-linked mucins, cysteine proteases (cruzipain), surface glycoproteins of the trans-sialidase family and/or parasite-derived eicosanoids (thromboxane A(2)). Initial insight into pathogenesis came from research in animal models showing that myocardial fibrosis is worsened as result of endothelin upregulation by infected cardiovascular cells. Paralleling these studies, the kinin system emerged as a proteolytic mechanism that links oedematogenic inflammation to immunity. Analyses of the dynamics of inflammation revealed that tissue culture trypomastigotes elicit interstitial oedema in peripheral sites of infection through synergistic activation of toll-like 2 receptors (TLR2) and G-protein-coupled bradykinin receptors, respectively, engaged by tGPI (TLR2 ligand) and kinin peptides (bradykinin B2 receptors (BK(2)R) ligands) proteolytically generated by cruzipain. Further downstream, kinins stimulate lymph node dendritic cells via G-protein-coupled BK(2)R, thus converting these specialized antigen-presenting cells into T(H)1 inducers. Tightly regulated by angiotensin-converting enzyme, the intact kinins (BK(2)R agonists) may be processed by carboxypeptidase M/N, generating [des-Arg]-kinins, which activates BK(1)R, a subtype of GPCR that is upregulated by cardiovascular cells during inflammation. Ongoing studies may clarify if discrepancies between proinflammatory phenotypes of T. cruzi strains may be ascribed, at least in part, to variable expression of TLR2 ligands and cruzipain isoforms.

• Authors: Julio Scharfstein, Daniele Andrade
• Journal: Advances in parasitology (Adv Parasitol) Vol. 76 Pg. 101-27 ( 2011) ISSN: 2163-6079 [Electronic] England
• PMID: 21884889 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Endothelins
• Inflammation Mediators
• Kinins
• Virulence Factors

Topics

• Animals
• Blood Vessels (pathology)
• Chagas Disease (immunology, parasitology, pathology)
• Endothelins (metabolism)
• Host-Parasite Interactions
• Humans
• Inflammation (immunology, parasitology)
• Inflammation Mediators (metabolism)
• Kinins (metabolism)
• Metabolic Networks and Pathways
• Trypanosoma cruzi (immunology, pathogenicity)
• Virulence Factors (immunology, metabolism)