IN VIVO PHARMACOLOGICAL INHIBITION OF WNT PROTEINS SECRETION DURING THE ACUTE PHASE OF T. CRUZI INFECTION REDUCES THE SEVERITY OF CHRONIC CHAGAS DISEASE CARDIOMYOPATHY IN BALB/C MICE.

VOLPINI, X; AMBROSIO, L; BRAJÍN, A; AOKI, MP; RIVAROLA, G; ALFONSO, F; FOSSATTI, L; MOTRAN, C

Exposici�n; REUNION ANUAL DE A SOCIEDAD ARGENTINA DE INMUNOLOGIA; 2018

Chagas disease is a major cause of heart disease andcardiovascular-related deaths in endemic areas locatedin Latin America. Each year there are approximately12,000 deaths which are attributable to Chagas disease,typically due to severe chronic Chagas diseasecardiomyopathy. Wnt signaling, essential for embryonicdevelopment, has also recently been involved in the regulationof inflammatory processes. We have previouslyreported that T. cruzi infection induces Wnt pathways activationand that in vivo pharmacological inhibition of theWnt proteins secretion controls the parasite replicationand improve the survival of lethally infected B6 mice. Toinvestigate the role on Wnt proteins in determining theoutcome of chronic Chagas disease, BALB/c mice wereinfected with 1,000 trypomastigotes of T. cruzi and treatedwith the inhibitor of Wnt secretion IWP-L6 (7.5 mg/kg) or vehicle (control) on days 5, 8, 11 and 14 post-infection(pi). During the acute phase of the infection,IWP-L6-treated mice showed lower levels of parasitemia (p<0.05), associated with increased serum levels of IL-12 (p<0.05) and TNF (p<0.001) and decreased functionof Treg cells (p<0.05) compared with control mice. At thechronic phase of the infection (180 days pi), the cardiacelectrophysiology and global left ventricular function (LV)were studied by electrocardiogram (ECG) and 2D-echocardiogram(ECHO), respectively. The ECGs of IWP-L6-treated mice were improved compared with control mice,because non-treated group presented a significant prolongationin the QT intervals (p<0.001), suggesting intraventricularconduction blockages; meanwhile, this abnormalitywas not observed in the IWP-L6-treated group.In addition, ECHO revealed systolic disfunction that wasonly present in control mice (p<0.01). Our results indicatethat the inhibition of Wnt proteins secretion duringthe acute phase of the infection might controls parasitereplication, thus preventing the development of chroniccardiomyopathy.