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

Mar del Plata

Congreso; Reunión Anual de Biociencias; 2022

Chagas disease is one of the most neglected tropical diseases, withcardiomyopathy 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 tissuevolume, but they account for only 30?40% of cell numbers. Theremaining 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 developmentof fibrosis-prone Th2-type immune response, and prevents the development of chronic Chagas disease?s cardiac abnormalities. Toevaluate whether T. cruzi infection induce in FB the expression ofgenes involved in Wnt signaling, NIH3T3 cells were infected with T.cruzi and the expression of Ctnnb1, Wnt3a, Wnt5a, Wisp1 and Axin1transcripts assessed at different times post infection (pi), using uninfected cells as control. The evaluation by means of q-PCR of thetranscripts corresponding to Wnt3a and the target genes Wisp1 andAxin1 revealed that at 3 hpi there is an increase in the transcriptionof this genes. In addition, increased transcription of Wnt5a and Ctnnb1 transcripts was observed at 6 hpi. Then, we studied whetherthe inhibition of Wnt signaling by block Wnt proteins secretion usingIWP-L6 or LGK9 regulates FB function by modulating the secretionof IL-1b, IL-6, and the production of NO and cytoplasmatic (c) or mitochondrial (m) ROS. Block of Wnt signaling increased the % of cellsproducing NO (DAF-FM+ cells) (p<0.05) and the production of IL-1band IL-6 (p<0.05), decreased the production of mROS (mitoSOX+cells) (p<0.05) and did not modify the cROS (H2DCFDA+ cells). Ourdata suggest that Wnt signaling is involved in the regulation of FBphenotype and function during T. cruzi infection.