Abstract
The mechanisms by which Trypanosoma cruzi survives antimicrobial peptides and differentiates during its transit through the gastrointestinal tract of the reduviid vector are unknown. We show that cyclophilin, a peptidyl-prolyl isomerase secreted from T. cruzi epimastigotes, binds to and neutralizes the reduviid antimicrobial peptide trialysin promoting parasite survival. This is dependent on a singular proline residue in trialysin and is inhibited by the cyclophilin inhibitor cyclosporine A. In addition, cyclophilin-trialysin complexes enhance the production of ATP and reductase responses of parasites, which are inhibited by both calcineurin-specific inhibitors cyclosporine A and FK506. Calcineurin phosphatase activity of cyclophilin-trialysin-treated parasites was higher than in controls and was inhibited by preincubation by either inhibitor. Parasites exposed to cyclophilin-trialysin have enhanced binding and invasion of host cells leading to higher infectivity. Leishmanial cyclophilin also mediates trialysin protection and metabolic stimulation by T. cruzi, indicating that extracellular cyclophilin may be critical to adaptation in other insect-borne protozoa. This work demonstrates that cyclophilin serves as molecular sensor leading to the evasion and adaptive metabolic response to insect defense peptides.
Highlights
The mechanisms of insect immune peptide recognition and evasion by T. cruzi are unknown
The conditioned medium from epimastigotes from one parasite strain stimulated the reductase activity of the epimastigotes of another parasite strain, indicating that the cationic antimicrobial peptides (CAMPs) response pathway functions in more than one T. cruzi isolate (Fig. 1B). We have found this pathway in CL, Y, Tulahuen, and Brazil strains of T. cruzi epimastigotes
The base-line bioenergetic activity of non-activated epimastigotes was partially affected by the inhibitor, whereas that from CAMP activation was completely ablated, indicating that parasites switched from mixed cytosolic and mitochondrial ATP production in resting parasites to predominately mitochondrial ATP production during CAMP activation
Summary
The mechanisms of insect immune peptide recognition and evasion by T. cruzi are unknown. A peptidyl-prolyl isomerase secreted from T. cruzi epimastigotes, binds to and neutralizes the reduviid antimicrobial peptide trialysin promoting parasite survival This is dependent on a singular proline residue in trialysin and is inhibited by the cyclophilin inhibitor cyclosporine A. We report our work on the interaction of CAMP with T. cruzi, which reveals a unique pathway of parasite-driven modification of host CAMP In this pathway we have found that secreted parasite cyclophilin, a peptidyl-prolyl isomerase, binds to and inactivates trialysin via action at its proline residue. Cyclophilin-trialysin synergistically acts on parasites to activate calcineurin phosphatase signaling, which drives metabolic activation and ATP production leading to enhanced infectivity This novel parasite pathway describes a mechanism of CAMP recognition, evasion, and adaptation mediated through calcineurin intracellular signaling
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