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Improving antichagasic drug discovery through stage-specific monitoring of Trypanosoma cruzi

English title Improving antichagasic drug discovery through stage-specific monitoring of Trypanosoma cruzi
Applicant Mäser Pascal
Number 164172
Funding scheme Brazil
Research institution Swiss Tropical and Public Health Institute Medical Services and Diagnostic Universität Basel
Institution of higher education University of Basel - BS
Main discipline Cellular Biology, Cytology
Start/End 01.03.2016 - 31.05.2019
Approved amount 249'088.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Experimental Microbiology

Keywords (6)

Trypanosoma cruzi; Posaconazole; Schistosoma mansoni; Chagas' disease; Reporter genes; Drug discovery

Responsible applicant and co-applicants

Employees

Project partner

Collaboration

Group / person Country
Types of collaboration
Santuza Maria Ribeiro Teixeira Brazil (South America)
- in-depth/constructive exchanges on approaches, methods or results
Prof. John Kelly Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Nicolas Fasel, UniL Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
DNDi Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Isabel Roditi Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Kinetoplastid Cell and Molecular Parasitology Meeting Poster Non-invasive monitoring of drug action: Exploring new assay designs for Chagas’ disease in vitro drug discovery 27.04.2019 Woods Hole, MA, United States of America Fesser Anna Frieda;
Swiss Trypanosomatid Meeting Talk given at a conference From growth curve to time-to-kill: exploring new in vitro assays for Chagas' disease 09.01.2019 Leysin, Switzerland Fesser Anna Frieda;
Swiss Trypanosomatid Meeting Poster Alive and green: Refing Trypanosoma cruzi in vitro drug screening assays 10.01.2018 Leysin, Switzerland Fesser Anna Frieda;
SSTMP Student Meeting Talk given at a conference Improving Trypanosoma cruzi in vitro screening 02.11.2017 Schwarzenberg, Switzerland Fesser Anna Frieda;
Annual Meeting Swiss Society of Tropical Medicine and Parasitology Poster A green fluorescent Trypanosoma cruzi line to increase sensitivity of in vitro drug screening assays 30.08.2017 Basel, Switzerland Fesser Anna Frieda;
Young Parasitologist Summer School Talk given at a conference Stage-specific reporter gene expression in Trypanosoma cruzi 07.08.2017 Bernhard-Nocht-Institute, Hamburg, Germany Fesser Anna Frieda;
Swiss Trypanosomatid Meeting Poster A Standardized Tool to the Trypanosoma cruzi Toolbox 11.01.2017 Leysin, Switzerland Fesser Anna Frieda;
BSP Trypanosomiasis and Leishmaniasis seminar Poster Stage-specific reporter gene expression in Trypanosoma cruzi 04.09.2016 Budweis, Czech Republic Fesser Anna Frieda;


Self-organised

Title Date Place
Swiss Trypanosomatid Meeting 11.01.2017 Leysin, Switzerland

Communication with the public

Communication Title Media Place Year
Other activities Wissensbox Mikroskopie German-speaking Switzerland 2019
Talks/events/exhibitions Uni am Markt German-speaking Switzerland 2017
Talks/events/exhibitions Fest der Moleküle German-speaking Switzerland 2016

Abstract

Trypanosoma cruzi is the causative agent of Chagas’ disease, endemic in 21 countries of Latin America. Migration and travel have distributed Chagas’ disease to other continents. In the absence of a vaccine, there is a high need for new antichagasic drugs. However, the latest clinical trials have yielded disappointing results as it became apparent that posaconazole, a highly potent compound in standard in vitro tests, was unable to cure chronic T. cruzi infections. Meanwhile the failure of posaconazole and other azoles to deliver sterile cidality has been reproduced in refined in vitro test systems that demonstrated surviving forms after posaconazole treatment. The nature of those forms and whether they play a role in vivo has been elusive. Here we propose to generate a T. cruzi reporter strain that expresses fluorescent proteins for in vitro monitoring, or luminescent proteins for in vivo imaging, in a stage-specific way, i.e. different colors in the replicating amastigote and the non-replicating trypomastigote forms of the mammalian host. Such a strain will allow to study stage-specificity of drug action and to better assess monotherapies and combinations for their potential to deliver sterile cure. It will also permit new insights into differentiation of T. cruzi in vivo and will allow to better understand phenomena of co-infection, which will be addressed here using previous Schistosoma mansoni infection in a T. cruzi mouse model. Thus the proposed research will give new insights into the biology of T. cruzi that directly translate into drug discovery tools of improved predictability for therapeutic success.
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