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

Published online by Cambridge University Press:  12 August 2021

Laura Lafon-Hughes Open the ORCID record for Laura Lafon-Hughes [Opens in a new window] ,
Silvia H. Fernández Villamil  and
Salomé C. Vilchez Larrea Open the ORCID record for Salomé C. Vilchez Larrea [Opens in a new window]
Laura Lafon-Hughes
Affiliation:
Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay Grupo de Biofisicoquímica, Departamento de Ciencias Biológicas, Centro Universitario Regional Litoral Norte, Universidad de la República (CENUR-UdelaR), Salto, Uruguay
Silvia H. Fernández Villamil*
Affiliation:
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ‘Dr. Héctor N. Torres’, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
Salomé C. Vilchez Larrea*
Affiliation:
Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ‘Dr. Héctor N. Torres’, Consejo Nacional de Investigaciones Científicas y Técnicas, Ciudad Autónoma de Buenos Aires, Argentina Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina
*
Author for correspondence: Salomé C. Vilchez Larrea, E-mail: [email protected]; Silvia H. Fernández Villamil, E-mail: [email protected]
Author for correspondence: Salomé C. Vilchez Larrea, E-mail: [email protected]; Silvia H. Fernández Villamil, E-mail: [email protected]
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Abstract

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 aetiological agent, Trypanosoma cruzi, displays varied cell invading tactics and triggers different host cell signals, including the Wnt/β-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 homoeostasis 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 and 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 T. cruzi induced nuclear translocation of β-catenin, as well as upregulation of TNF-α expression and secretion. These changes were hampered by TNKSi. Further signals should be monitored in this model and in vivo. As a TNKSi has entered cancer clinical trials with promising results, our findings encourage further studies aiming at drug repurposing strategies.

Keywords

Chagas diseasehost–pathogen interactionPARPTankyrase inhibitorsTrypanosoma cruziβ-catenin signalling
Type
Research Article
Information
Parasitology , Volume 148 , Issue 13 , November 2021 , pp. 1680 - 1690
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Copyright
Copyright © The Author(s), 2021. Published by Cambridge University Press

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