TRYPANOSOMA CRUZI INFECTION: TRANSCRIPTIONAL ANALYSIS REVEALS A ROLE OF WNT SIGNALING PATHWAYS IN MACROPHAGE POLARIZATION AND FUNCTION

BRUGO, MARÍA BELEN; NATALI, L; VOLPINI, XIMENA; JUAN NAHUEL QUIROZ; AMBROSIO, LAURA F.; TJON LF; QUINTANA, FRANCISCO; CLAUDIA MOTRAN

Virtual

Congreso; Reunión anual de Sociedades de Biociencias; 2020

SAI-SAIC

Mo activated by pro-inflammatory cytokines (classically activated or M1 Mo) upregulates different effective defense mechanisms against T. cruzi and plays a key role in the control of intracellular parasite growth. However, through the modulation of several signaling path- ways, the parasite subverts the Mo polarization to favor its surviv- al. We have reported that T. cruzi infection induces β-catenin and Wnt/Ca++ pathways activation in Mo, with these pathways being critical to sustaining intracellular parasite replication. Moreover, the inhibition of β-catenin transcriptional activity (using CCT036477 or iCRT14) or Wnt proteins secretion (using IWP-L6) modulates Mo ac- tivation status towards a more microbicidal phenotype, which does not fully fit in the classically activated/inflammatory M1 one.In the present study we evaluated the transcriptional profiles of non-infected, and infected Mo previously treated with CCT, iCRT, IWP-L6 or LPS+IFN-g (M1) (n= 3 replicates), compared their tran- scriptomes with M1 and M2 signature genes and performed gene set enrichment analysis (GSEA). Hierarchical clustering analysis revealed that infected IWP-L6 Mo are transcriptionally more similar to infected M1 Mo than infected CCT or iCRT Mo, which are clearly separated from control Mo and non-infected ones. Infection with T. cruzi up-regulated a M1-specific set of genes, while the inhibition of Wnt proteins secretion or β-catenin transcriptional activity showed down-regulated expression of them. In addition, GSEA revealed that inhibition of Wnt proteins secretion or β-catenin transcriptional activ- ity modulated the transcription of genes related to innate immune re- ceptors (TLR, NOD), cytokine and chemokine signaling, apoptosis, antigen processing and presentation, metabolism, and phagocyto- sis, between others. These results confirmed through transcriptional analysis our previous findings that during T. cruzi infection Wnt sig- naling contributes to modulate Mo polarization and function.