INHIBITION OF WNT SIGNALING PATHWAY CONTROLS PARASITE REPLICATION AND INFECTION-INDUCED PATHOLOGY DURING TRYPANOSOMA CRUZI INFECTION.

FOZZATTI, LAURA; VOLPINI, XIMENA; INSFRÁN, CONSTANZA; AMBROSIO, LAURA; MOTRÁN, CRISTINA

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Inmunología; 2016

The control of T. cruzi parasitism during the acute phase of 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) enzymes activity. Wnt/Frizzled signaling pathway is induced in Mo by inflammatory stimulus and signal through Wnt/b-catenin (canonical) and b-catenin-independent pathways to amplify or control the inflammation. We have shown that T. cruzi infection induces Wnt3a and Wnt5a expression and activates the b-catenin signalling pathway. Nonetheless, the modulation of Frizzled (Fzd) receptors and other Wnt proteins expression as well as the activation of b-catenin-independent pathways by T. cruzi infection in Mo remains unknown. In the present study we performed a RT Profiler PCR array to determine the T. cruzi infection-induced gene expression profiles of WNT signalling pathways in Mo and evaluated the role of b-catenin pathway activation on intracellular T. cruzi replication. After 12h of in vitro Mo infection (Tp:Mo= 3:1), several Fzd receptors, Wnt proteins and pathways-specific genes were differentially expressed on infected Mo, with Wnt/calcium (which inhibits canonical pathway) and b-catenin signalling pathways showing inhibition and activation respectively. Then, the canonical pathway was activated or inhibited using ClLi and BIO or iCRT14 respectively and the parasite replication and the activity of iNOS, arginase and IDO enzymes evaluated. Canonical pathway inhibition controlled intracellular parasite replication (p=0.03), increased IDO activity (p=0.05) and did not affect iNOS and arginase activities. Modulation of Wnt/Frizzled pathways may allow the design of new therapeutic strategiesto control T. cruzi replication.