TRYPANOSOMA CRUZI INFECTION: ROLE OF WNT SIGNALING IN THE MODULATION OF FIBROBLAST PHENOTYPE AND FUNCTION

BRUGO, MARÍA BELEN; JUAN NAHUEL QUIROZ; BAIGORRI, E; HERRERA, MELISA; VOLPINI, XIMENA; CLAUDIA MOTRAN

Mar del Plata

Congreso; Reunión anual de Sociedades de Biociencias; 2022

SAI-SAIC-FAIC

Chagas disease is one of the most neglected tropical diseases, with cardiomyopathy being the main cause of death in T. cruzi-infected patients. As the parasite actively replicates in cardiomyocytes, the heart remains a key target organ in the pathogenesis. Cardiomyocytes occupy approximately 75% of normal myocardial tissue volume, but they account for only 30?40% of cell numbers. The remaining cells are predominantly fibroblasts (FB). We have reported that in vivo inhibition of Wnt signaling by treatment with IWP-L6 (an inhibitor of Wnt proteins secretion) during the acute phase of T. cruzi infection controls the parasite load, inhibits the development of fibrosis-prone Th2-type immune response, and prevents the development of chronic Chagas disease?s cardiac abnormalities. To evaluate whether T. cruzi infection induce in FB the expression of genes involved in Wnt signaling, NIH3T3 cells were infected with T. cruzi and the expression of Ctnnb1, Wnt3a, Wnt5a, Wisp1 and Axin1 transcripts assessed at different times post infection (pi), using uninfected cells as control. The evaluation by means of q-PCR of the transcripts corresponding to Wnt3a and the target genes Wisp1 and Axin1 revealed that at 3 hpi there is an increase in the transcription of this genes. In addition, increased transcription of Wnt5a and Ctnnb1 transcripts was observed at 6 hpi. Then, we studied whether the inhibition of Wnt signaling by block Wnt proteins secretion using IWP-L6 or LGK9 regulates FB function by modulating the secretion of IL-1, IL-6, and the production of NO and cytoplasmatic (c) or mitochondrial (m) ROS. Block of Wnt signaling increased the % of cells producing NO (DAF-FM+ cells) (p