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Drug resistance in African trypanosomes - from the lab to the field and back

English title Drug resistance in African trypanosomes - from the lab to the field and back
Applicant Mäser Pascal
Number 156264
Funding scheme Project funding (Div. I-III)
Research institution Swiss Tropical and Public Health Institute Medical Services and Diagnostic Universität Basel
Institution of higher education University of Basel - BS
Main discipline Molecular Biology
Start/End 01.07.2015 - 31.03.2019
Approved amount 352'000.00
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All Disciplines (2)

Discipline
Molecular Biology
Experimental Microbiology

Keywords (12)

Diamidine; Genomics; Drug resistance; Suramin; Molecular mechanism; Aquaporin; Arsenical; Trypanosoma brucei; Pentamidine; Melarsoprol; Human African trypanosomiasis; Sleeping sickness

Lay Summary (German)

Lead
Die Schlafkrankheit ist eine tödliche Infektionskrankheit. Verursacht wird sie durch den Parasiten Trypanosoma brucei und übertragen durch die Tsetsefliegen, welche ausschliesslich in Afrika vorkommen. Das Projekt untersucht die Medikamentenresistenz bei T. brucei auf molekularer Ebene und leistet dadurch einen Beitrag an die Nachhaltigkeit in der Behandlung der Schlafkrankheit.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Die Behandlung der Schlafkrankheit beruht auf den Wirkstoffen Pentamidin und Suramin für das frühe, haemolymphatische Stadium, respektive auf Melarsoprol und Nifurtimox/Eflornithine für zerebrale Infektionen. Wir haben Laborstämme von T. brucei auf Resistenz gegenüber Suramin, Pentamidin und Melarsoprol selektioniert. Ein erstes Ziel ist es, durch vergleichende Genomik und reverse Genetik diejenigen Mutationen zu finden, welche für die Resistenz verantwortlich sind. Dann wird geprüft, ob solche Mutationen auch bei klinischen T. brucei Isolaten vorkommen. Schliesslich muss untersucht werden, ob das Auftreten solcher Mutionen mit Therapieversagen korreliert. Dies konnten wir am Beispiel von Mutationen im Aquaporin-2 Gen und Melarsoprolresistenz zeigen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Unsere Resultate werfen einerseits ein neues Licht auf die Funktion von Aquaporinen, andererseits sind sie anwendbar zur frühzeitigen Erkennung von Medikamentenresistenz mittels DNS-basierender Tests. Dass Medikamentenresistenz ein grosses Risiko für die Kontrolle von Infektionskrankheiten darstellt, ist den Medien bewusst geworden, was diesem Projekt auch einen gesellschaftlichen Kontext in der Schweiz verleiht.

Key words

Trypanosoma brucei, Schlafkrankheit, Medikamentenresistenz, Melarsoprol, Pentamidin, Suramin, Aquaporin
Direct link to Lay Summary Last update: 19.03.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Come, sweet death: targeting glycosomal protein import for antitrypanosomal drug development
Kalel Vishal C, Mäser Pascal, Sattler Michael, Erdmann Ralf, Popowicz Grzegorz M (2018), Come, sweet death: targeting glycosomal protein import for antitrypanosomal drug development, in Current Opinion in Microbiology, 46, 116-122.
Beyond immune escape: a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei Suramin resistance in T . brucei
Wiedemar Natalie, Graf Fabrice E., Zwyer Michaela, Ndomba Emiliana, Kunz Renggli Christina, Cal Monica, Schmidt Remo S., Wenzler Tanja, Mäser Pascal (2018), Beyond immune escape: a variant surface glycoprotein causes suramin resistance in Trypanosoma brucei Suramin resistance in T . brucei, in Molecular Microbiology, 107(1), 57-67.
Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity
Jeacock Laura, Baker Nicola, Wiedemar Natalie, Mäser Pascal, Horn David (2017), Aquaglyceroporin-null trypanosomes display glycerol transport defects and respiratory-inhibitor sensitivity, in PLOS Pathogens, 13(3), e1006307-e1006307.
Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense
Graf Fabrice E., Ludin Philipp, Arquint Christian, Schmidt Remo S., Schaub Nadia, Kunz Renggli Christina, Munday Jane C., Krezdorn Jessica, Baker Nicola, Horn David, Balmer Oliver, Caccone Adalgisa, de Koning Harry P., Mäser Pascal (2016), Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense, in Cellular and Molecular Life Sciences, 73(17), 3387-3400.

Collaboration

Group / person Country
Types of collaboration
Prof. David Horn, University of Dundee Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Isabel Roditi, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Mark Field, University of Dundee Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
36th Swiss Trypanosomatid Meeting Talk given at a conference Expression of a specific variant surface glycoprotein has a major impact on suramin sensitivity and endocytosis in Trypanosoma brucei 09.01.2019 Leysin, Switzerland Wiedemar Natalie; Mäser Pascal;
BSP Spring Meeting 2018; short talk by Natalie Wiedemar, keynote by Pascal Mäser Talk given at a conference More than immune evasion – a variant surface glycoprotein causes in vitro suramin resistance in Trypanosoma brucei 28.04.2018 Aberystwyth, Great Britain and Northern Ireland Mäser Pascal; Wiedemar Natalie;
28th Annual Meeting of the German Society for Parasitology Talk given at a conference More than immune evasion – a variant surface glycoprotein causes in vitro suramin resistance in Trypanosoma brucei 21.03.2018 Berlin, Germany Cal Monica;
35th Swiss trypanosomatid meeting Talk given at a conference VSGs – more than immune escape 10.01.2018 Leysin, Switzerland Wiedemar Natalie; Mäser Pascal;
Basel LIFE 2017 – EMBO Talk given at a conference Flash talk: A new link between drug susceptibility and antigenic variation in Trypanosoma brucei 11.09.2017 Basel, Switzerland Cal Monica;
Joint Annual Meeting SSM | SSI | SSHH | SSTMP | SSTTM Poster A new link between drug susceptibility and antigenic variation in Trypanosoma brucei 30.08.2017 Basel, Switzerland Wiedemar Natalie;
Kinetoplastid Molecular Cell Biology Meeting Poster Suramin resistance is associated with a VSG switch in Trypanosoma brucei 21.04.2017 Woods Hole, United States of America Cal Monica;
34th Swiss trypanosomatid meeting Talk given at a conference Transcriptomics of suramin resistance in African trypanosomes 11.01.2017 Leysin, Switzerland Mäser Pascal; Wiedemar Natalie;
BSP Trypanosomiasis and Leishmaniasis Seminar Poster Forward Genetics of Suramin Resistance in African Trypanosomes 04.09.2016 Budweis, Czech Republic Wiedemar Natalie;
33th Swiss trypanosomatid meeting Talk given at a conference Talk 20.01.2016 Leysin, Switzerland Mäser Pascal; Wiedemar Natalie;
European Congress on Tropical Medicine and International Health Talk given at a conference Session chair and moderator of discussion 06.09.2015 Basel, Switzerland Mäser Pascal;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
BioValley College Network - Life Science Symposium Workshop 17.03.2018 Gymnasium Bäumlihof, Riehen, Switzerland Mäser Pascal;


Awards

Title Year
2nd prize for best student presentation Swiss Trypanosomatid Meeting, Leysin 2019
PhD summa cum laude 2019
2nd prize for best student presentation Swiss Trypanosomatid Meeting, Leysin 2018

Associated projects

Number Title Start Funding scheme
185163 Molecular mechanisms of suramin resistance in Trypanosoma brucei 01.10.2019 Project funding (Div. I-III)
135746 Drug resistance in African trypanosomes - a deep sequencing approach 01.07.2011 Project funding (Div. I-III)
135746 Drug resistance in African trypanosomes - a deep sequencing approach 01.07.2011 Project funding (Div. I-III)
141913 Transporters of Trypanosoma brucei: Phylogeny - Physiology - Pharmacology 01.06.2013 Sinergia

Abstract

Human African trypanosomiasis (HAT, also known as sleeping sickness) is caused by the haemoflagellate parasites Trypanosoma brucei rhodesiense and T. b. gambiense, and transmitted by the tsetse fly. It is a fatal disease, there is no vaccine, and the available drugs are not satisfactory due to their adverse effects and lack of oral bioavailability. Nevertheless, the prevalence is reclining and HAT may actually be one of the few parasitoses that can be eliminated. This, however, will require new and better drugs. Until then, the current drugs pentamidine, suramin, melarsoprol, and eflornithine/nifurtimox need to be used in a sustainable way, which requires an understanding of the molecular mechanisms of drug resistance. In our current SNF grant we have been investigating the well-known phenomenon of melarsoprol/pentamidine cross-resistance (MPXR) by comparative genomics of susceptible and resistant T. b. rhodesiense lines. We have identified a new point mutation in the adenosine transporter gene TbAT1 that may be involved in drug resistance, and we have demonstrated that the aquaglyceroporin TbAQP2 is missing in the MPXR T. b. rhodesiense. Clinical T. b. gambiense isolates with an MPXR phenotype had a mutant version of the aquaglyceroporin, a chimera between the two tandem genes TbAQP2 and TbAQP3. The MPXR T. b. rhodesiense carried a further mutation, arginine131 to leucin in the RNA-binding protein TbUBP1. Finally, we have generated three stable, isogenic T. b. rhodesiense lines that are resistant to suramin and cross-resistant to trypan blue. Here we propose to continue and possibly finish these lines of research. We shall determine the individual and combined effects on MPXR of the mutations detected in the lab, investigate the function of the newly identified TbAQP2 / TbAQP3 chimera, and test whether the observed MPXR phenotype in the field can be reverted by expression of wild-type TbAQP2. The mutations underlying suramin resistance will be studied by transcriptome sequencing. The anticipated results will be directly applicable to the field and at the same time provide fundamental insights into the biology and pharmacology of trypanosomes.
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