Subverting bradykinin-evoked inflammation by co-opting the contact system: lessons from survival strategies of Trypanosoma cruzi

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Abstract

Purpose of review

During Chagas disease, Trypanosoma cruzi alternates between intracellular and extracellular developmental forms. After presenting an overview about the roles of the contact system in immunity, I will review experimental studies showing that activation of the kallikrein-kinin system (KKS) translates into mutual benefits to the host/parasite relationship.

Recent findings

T. cruzi trypomastigotes initiate inflammation by activating tissue-resident innate sentinel cells via the TLR2/CXCR2 pathway. Following neutrophil-evoked microvascular leakage, the parasite's major cysteine protease (cruzipain) cleaves plasma-borne kininogens and complement C5. Tightly regulated by angiotensin-converting enzyme (ACE), kinins and C5a in turn further propagate inflammation via iterative cycles of mast cell degranulation, contact system activation, bradykinin release and activation of endothelial bradykinin B2 receptors (B2R). Recently, studies in the intracardiac model of infection revealed a dichotomic role for bradykinin and endothelin-1: generated upon contact activation (mast cell/KKS pathway), these pro-oedematogenic peptides reciprocally stimulate trypomastigote invasion of heart cells that naturally overexpress B2R and endothelin receptors (ETaR/ETbR).

Summary

Studies focusing on the immunopathogenesis of Chagas disease revealed that the contact system plays a dual role in host/parasite balance: T. cruzi co-opts bradykinin-induced plasma leakage as a strategy to increment heart parasitism and increase immune resistance by upregulating type-1 effector T-cell production in secondary lymphoid tissues.

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