Tankyrase inhibitors hinder Trypanosoma cruzi infection by altering host-cell signalling pathways

Chagas disease is a potentially life-threatening protozoan infection affecting around 8 million people, for which only chemotherapies with limited efficacy and severe adverse secondary effects are available. The etiological agent, Trypanosoma cruzi, displays varied cell invading tactics and triggers different host cell signals, including the Wnt/b-catenin pathway. Poly(ADP-ribose) (PAR) can be synthetized by certain members of the poly(ADP-ribose) polymerase (PARP) family: PARP-1/-2 and Tankyrases-1/2 (TNKS). PAR homeostasis participates in the host cell response to T. cruzi infection and TNKS are involved in Wnt signalling, among other pathways. Therefore, we hypothesized that TNKS inhibitors (TNKSi) could hamper T. cruzi infection. We showed that five TNKSi (FLALL9, MN64, XAV939, G007LK & OULL9) diminished T. cruzi infection of Vero cells. As most TNKSi did not affect the viability of axenically cultivated parasites, our results suggested that TNKSi were interfering with parasite-host cell signalling. Infection by Trypanosoma cruzi induced nuclear translocation of b-catenin, as well as up-regulation of TNF-a expression and secretion. These changes were hampered by TNKSi. Further signals should be monitored in this model and in vivo. As a TNKS inhibitor has entered cancer clinical trials with promising results, our findings encourage further studies aiming at drug repurposing strategies.Fil: Lafon Hughes, Laura. Universidad de la República; UruguayFil: Fernandez Villamil, Silvia Hebe. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Química Biológica; ArgentinaFil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentin