T. cruzi-induced Wnt/B catenin signaling pathway activation promotes parasite replication in macrophages

VOLPINI, XIMENA; AMBROSIO, LF; FOZZATTI, LAURA; INSFRAN, CONSTANZA; MOTRAN, CLAUDIA C

CABA

Congreso; I meeting LASID SAI FAIC; 2015

LASID SAI

The control of T.cruzi parasitism during the acute phaseof infection is critically dependent on effective macrophage (Mo)activation and the up-regulation of indoleamine 2,3 dioxigenase(IDO) and the inducible nitric oxide synthase (iNOS) enzymesactivity. Wnt/Frizzled signaling pathway is induced in Mo byinflammatory stimulus and signal through Wnt/β-catenin(canonical) and β-catenin-independent pathways to amplify orcontrol the inflammation. We have shown that T.cruzi infectioninduces Wnt3a and Wnt5a expression and activates the β-cateninsignaling pathway. Nonetheless, the modulation of Frizzled (Fzd)receptors and other Wnt proteins expression, as well as theactivation of β-catenin-independent pathways by T.cruzi infectionin Mo, remains unknown. In the present study we performed a RTProfiler PCR array to determine the T.cruzi infection-inducedgene expression profiles of WNT signaling pathways in Mo andevaluated the role of β-catenin pathway activation on intracellularT.cruzi replication. After 12 h of in vitro Mo infection (Tp:Mo=3:1), several Fzd receptors, Wnt proteins and pathways-specificgenes were differentially expressed on infected Mo, withWnt/calcium (which inhibits canonical pathway) and β-cateninsignaling pathways showing inhibition and activation respectively.Then, the canonical pathway was activated or inhibited using ClLiand BIO or iCRT14 respectively and the parasite replication andthe activity of iNOS, arginase and IDO enzymes evaluated.Canonical pathway inhibition controlled intracellular parasitereplication (p=0.03), increased IDO activity (p=0.05) and didn?taffect iNOS and arginase activities. Modulation of Wnt/Frizzledpathways may allow the design of new therapeutic strategies tocontrol T.cruzi replication.