FIGURE 8.

Model of secreted cyclophilin-mediated sensing and adaptation to insect CAMP. Step 1, replicating T. cruzi epimastigotes secrete cyclophilin 19 extracellularly, which binds to insect host proline-containing CAMP, such as trialysin (indicated with P surrounded by a box) (see Figs. 1 and 2). Step 2, the binding and proline isomerization of trialysin inactivates the CAMP and protects parasites from trypanocidal action. Step 3, cyclophilin 19-trialysin complexes feed back on parasites by action on the membrane to trigger intracellular calcineurin phosphatase activation (large box with lightening bolt) (see Fig. 3). This leads to the downstream metabolic responses of increased ATP and reductase activity, stoppage of cell division, and MET-III expression (see Fig. 4), which contributes to enhanced parasite infectivity. We hypothesize that the interaction of cyclophilin 19 with other protein ligands, such as proline-containing defensin-like peptides (5, 62, 63) or α-globin (1, 29, 51), may also contribute to aspects of in vivo parasite differentiation.