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2021
Schorn, Michelle A; Verhoeven, Stefan; Ridder, Lars; Huber, Florian; Acharya, Deepa D; Aksenov, Alexander A; Aleti, Gajender; Moghaddam, Jamshid Amiri; Aron, Allegra T; Aziz, Saefuddin; Bauermeister, Anelize; Bauman, Katherine D; Baunach, Martin; Beemelmanns, Christine; Beman, Michael J; Berlanga-Clavero, María Victoria; Blacutt, Alex A; Bode, Helge B; Boullie, Anne; Brejnrod, Asker; Bugni, Tim S; Calteau, Alexandra; Cao, Liu; Carrión, Víctor J; Castelo-Branco, Raquel; Chanana, Shaurya; Chase, Alexander B; Chevrette, Marc G; Costa-Lotufo, Leticia V; Crawford, Jason M; Currie, Cameron R; Cuypers, Bart; Dang, Tam; de Rond, Tristan; Demko, Alyssa M; Dittmann, Elke; Du, Chao; Drozd, Christopher; Dujardin, Jean-Claude; Dutton, Rachel J; Edlund, Anna; Fewer, David P; Garg, Neha; Gauglitz, Julia M; Gentry, Emily C; Gerwick, Lena; Glukhov, Evgenia; Gross, Harald; Gugger, Muriel; Matus, Dulce G Guillén; Helfrich, Eric J N; Hempel, Benjamin-Florian; Hur, Jae-Seoun; Iorio, Marianna; Jensen, Paul R; Kang, Kyo Bin; Kaysser, Leonard; Kelleher, Neil L; Kim, Chung Sub; Kim, Ki Hyun; Koester, Irina; König, Gabriele M; Leao, Tiago; Lee, Seoung Rak; Lee, Yi-Yuan; Li, Xuanji; Little, Jessica C; Maloney, Katherine N; Männle, Daniel; H., Christian Martin; McAvoy, Andrew C; Metcalf, Willam W; Mohimani, Hosein; Molina-Santiago, Carlos; Moore, Bradley S; Mullowney, Michael W; Muskat, Mitchell; Nothias, Louis-Félix; O'Neill, Ellis C; Parkinson, Elizabeth I; Petras, Daniel; Piel, Jörn; Pierce, Emily C; Pires, Karine; Reher, Raphael; Romero, Diego; Roper, Caroline M; Rust, Michael; Saad, Hamada; Saenz, Carmen; Sanchez, Laura M; Sørensen, Søren Johannes; Sosio, Margherita; Süssmuth, Roderich D; Sweeney, Douglas; Tahlan, Kapil; Thomson, Regan J; Tobias, Nicholas J; Trindade-Silva, Amaro E; van Wezel, Gilles P; Wang, Mingxun; Weldon, Kelly C; Zhang, Fan; Ziemert, Nadine; Duncan, Katherine R; Crüsemann, Max; Rogers, Simon; Dorrestein, Pieter C; Medema, Marnix H; van der Hooft, Justin J J
A community resource for paired genomic and metabolomic data mining Journal Article
In: Nature Chemical Biology, 2021, ISSN: 1552-4469.
@article{Schorn2021,
title = {A community resource for paired genomic and metabolomic data mining},
author = {Michelle A Schorn and Stefan Verhoeven and Lars Ridder and Florian Huber and Deepa D Acharya and Alexander A Aksenov and Gajender Aleti and Jamshid Amiri Moghaddam and Allegra T Aron and Saefuddin Aziz and Anelize Bauermeister and Katherine D Bauman and Martin Baunach and Christine Beemelmanns and Michael J Beman and Mar\'{i}a Victoria Berlanga-Clavero and Alex A Blacutt and Helge B Bode and Anne Boullie and Asker Brejnrod and Tim S Bugni and Alexandra Calteau and Liu Cao and V\'{i}ctor J Carri\'{o}n and Raquel Castelo-Branco and Shaurya Chanana and Alexander B Chase and Marc G Chevrette and Leticia V Costa-Lotufo and Jason M Crawford and Cameron R Currie and Bart Cuypers and Tam Dang and Tristan de Rond and Alyssa M Demko and Elke Dittmann and Chao Du and Christopher Drozd and Jean-Claude Dujardin and Rachel J Dutton and Anna Edlund and David P Fewer and Neha Garg and Julia M Gauglitz and Emily C Gentry and Lena Gerwick and Evgenia Glukhov and Harald Gross and Muriel Gugger and Dulce G Guill\'{e}n Matus and Eric J N Helfrich and Benjamin-Florian Hempel and Jae-Seoun Hur and Marianna Iorio and Paul R Jensen and Kyo Bin Kang and Leonard Kaysser and Neil L Kelleher and Chung Sub Kim and Ki Hyun Kim and Irina Koester and Gabriele M K\"{o}nig and Tiago Leao and Seoung Rak Lee and Yi-Yuan Lee and Xuanji Li and Jessica C Little and Katherine N Maloney and Daniel M\"{a}nnle and Christian Martin H. and Andrew C McAvoy and Willam W Metcalf and Hosein Mohimani and Carlos Molina-Santiago and Bradley S Moore and Michael W Mullowney and Mitchell Muskat and Louis-F\'{e}lix Nothias and Ellis C O'Neill and Elizabeth I Parkinson and Daniel Petras and J\"{o}rn Piel and Emily C Pierce and Karine Pires and Raphael Reher and Diego Romero and Caroline M Roper and Michael Rust and Hamada Saad and Carmen Saenz and Laura M Sanchez and S\oren Johannes S\orensen and Margherita Sosio and Roderich D S\"{u}ssmuth and Douglas Sweeney and Kapil Tahlan and Regan J Thomson and Nicholas J Tobias and Amaro E Trindade-Silva and Gilles P van Wezel and Mingxun Wang and Kelly C Weldon and Fan Zhang and Nadine Ziemert and Katherine R Duncan and Max Cr\"{u}semann and Simon Rogers and Pieter C Dorrestein and Marnix H Medema and Justin J J van der Hooft},
url = {https://doi.org/10.1038/s41589-020-00724-z},
doi = {10.1038/s41589-020-00724-z},
issn = {1552-4469},
year = {2021},
date = {2021-02-15},
journal = {Nature Chemical Biology},
abstract = {Genomics and metabolomics are widely used to explore specialized metabolite diversity. The Paired Omics Data Platform is a community initiative to systematically document links between metabolome and (meta)genome data, aiding identification of natural product biosynthetic origins and metabolite structures.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Hefnawy, Aya; Negreira, Gabriel; Jara, Marlene; Cotton, James A; Maes, Ilse; Haenens, Erika Dtextquoteright; Imamura, Hideo; Cuypers, Bart; Monsieurs, Pieter; Mouchtoglou, Christina; Winter, Hans De; Berriman, Matt; Sanders, Mandy; Martin, Julio; de Muylder, Geraldine; Dujardin, Jean-Claude; Sterckx, Yann G -J; Domagalska, Malgorzata Anna
In: bioRxiv, 2021.
@article{Hefnawy2021.01.05.425522,
title = {Genomic and phenotypic characterization of experimentally selected resistant Leishmania donovani reveals a role for dynamin-1 like protein in the mechanism of resistance to a novel anti-leishmanial compound},
author = {Aya Hefnawy and Gabriel Negreira and Marlene Jara and James A Cotton and Ilse Maes and Erika D{textquoteright} Haenens and Hideo Imamura and Bart Cuypers and Pieter Monsieurs and Christina Mouchtoglou and Hans De Winter and Matt Berriman and Mandy Sanders and Julio Martin and Geraldine de Muylder and Jean-Claude Dujardin and Yann G -J Sterckx and Malgorzata Anna Domagalska},
url = {https://www.biorxiv.org/content/early/2021/01/06/2021.01.05.425522},
doi = {10.1101/2021.01.05.425522},
year = {2021},
date = {2021-01-01},
journal = {bioRxiv},
publisher = {Cold Spring Harbor Laboratory},
abstract = {The implementation of prospective drug resistance (DR) studies in the R\&D pipelines is a common practice for many infectious diseases, but not for Neglected Tropical Diseases. Here, we explored and demonstrated the importance of this approach, using as paradigms Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK textquoteleftLeishboxtextquoteright to treat VL. We experimentally selected resistance to TCMDC-143345 in vitro and characterized resistant parasites at genomic and phenotypic levels. We found that it took more time to develop resistance to TCMDC-143345 than to other drugs in clinical use and that there was no cross resistance to these drugs, suggesting a new and unique mechanism. By whole genome sequencing, we found two mutations in the gene encoding the L. donovani dynamin-1-like protein (LdoDLP1) that were fixed at highest drug pressure. Through phylogenetic analysis, we identified LdoDLP1 as a family member of the dynamin-related proteins, a group of proteins that impacts the shapes of biological membranes by mediating fusion and fission events, with a putative role in mitochondrial fission. We found that L. donovani lines genetically engineered to harbor the two identified LdoDLP1 mutations were resistant to TCMDC-143345 and displayed altered mitochondrial properties. By homology modeling, we showed how the two LdoDLP1 mutations may influence protein structure and function. Taken together, our data reveal a clear involvement of LdoDLP1 in the adaptation/resistance of L. donovani to TCMDC-143345.Importance Humans and their pathogens are continuously locked in a molecular arms race during which the eventual emergence of pathogen drug resistance (DR) seems inevitable. For neglected tropical diseases (NTDs), DR is generally studied retrospectively, once it has already been established in clinical settings. We previously recommended to keep one step ahead in the host-pathogen arms race and implement prospective DR studies in the R\&D pipeline, a common practice for many infectious diseases, but not for NTDs. Here, using Leishmania donovani, the etiological agent of Visceral Leishmaniasis (VL), and TCMDC-143345, a promising compound of the GSK textquoteleftLeishboxtextquoteright to treat VL, as paradigms, we experimentally selected resistance to the compound and proceeded to genomic and phenotypic characterization of DR parasites. The results gathered in the present study suggest a new DR mechanism involving the L. donovani dynamin-1 like protein (LdoDLP1) and demonstrate the practical relevance of prospective DR studies.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Boullosa, Laurie Freire; Loenhout, Jinthe Van; Flieswasser, Tal; Waele, Jorrit De; Hermans, Christophe; Lambrechts, Hilde; Cuypers, Bart; Laukens, Kris; Bartholomeus, Esther; Siozopoulou, Vasiliki; Vos, Winnok H De; Peeters, Marc; Smits, Evelien L J; Deben, Christophe
In: Redox Biology, pp. 101949, 2021, ISSN: 2213-2317.
@article{BOULLOSA2021101949,
title = {Auranofin reveals therapeutic anticancer potential by triggering distinct molecular cell death mechanisms and innate immunity in mutant p53 non-small cell lung cancer},
author = {Laurie Freire Boullosa and Jinthe Van Loenhout and Tal Flieswasser and Jorrit De Waele and Christophe Hermans and Hilde Lambrechts and Bart Cuypers and Kris Laukens and Esther Bartholomeus and Vasiliki Siozopoulou and Winnok H De Vos and Marc Peeters and Evelien L J Smits and Christophe Deben},
url = {https://www.sciencedirect.com/science/article/pii/S2213231721000975},
doi = {https://doi.org/10.1016/j.redox.2021.101949},
issn = {2213-2317},
year = {2021},
date = {2021-01-01},
journal = {Redox Biology},
pages = {101949},
abstract = {Auranofin (AF) is an FDA-approved antirheumatic drug with anticancer properties that acts as a thioredoxin reductase 1 (TrxR) inhibitor. The exact mechanisms through which AF targets cancer cells remain elusive. To shed light on the mode of action, this study provides an in-depth analysis on the molecular mechanisms and immunogenicity of AF-mediated cytotoxicity in the non-small cell lung cancer (NSCLC) cell line NCI-H1299 (p53 Null) and its two isogenic derivates with mutant p53 R175H or R273H accumulation. TrxR is highly expressed in a panel of 72 NSCLC patients, making it a valid druggable target in NSCLC for AF. The presence of mutant p53 overexpression was identified as an important sensitizer for AF in (isogenic) NSCLC cells as it was correlated with reduced thioredoxin (Trx) levels in vitro. Transcriptome analysis revealed dysregulation of genes involved in oxidative stress response, DNA damage, granzyme A (GZMA) signaling and ferroptosis. Although functionally AF appeared a potent inhibitor of GPX4 in all NCI-H1299 cell lines, the induction of lipid peroxidation and consequently ferroptosis was limited to the p53 R273H expressing cells. In the p53 R175H cells, AF mainly induced large-scale DNA damage and replication stress, leading to the induction of apoptotic cell death rather than ferroptosis. Importantly, all cell death types were immunogenic since the release of danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation occurred irrespective of (mutant) p53 expression. Finally, we show that AF sensitized cancer cells to caspase-independent natural killer cell-mediated killing by downregulation of several key targets of GZMA. Our data provides novel insights on AF as a potent, clinically available, off-patent cancer drug by targeting mutant p53 cancer cells through distinct cell death mechanisms (apoptosis and ferroptosis). In addition, AF improves the innate immune response at both cytostatic (natural killer cell-mediated killing) and cytotoxic concentrations (dendritic cell maturation).},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2020
Cuypers, Bart; Dumetz, Franck; Meysman, Pieter; Laukens, Kris; Muylder, Géraldine De; Dujardin, Jean-Claude; Domagalska, Malgorzata Anna
The Absence of C-5 DNA Methylation in Leishmania donovani Allows DNA Enrichment from Complex Samples Journal Article
In: Microorganisms, vol. 8, no. 8, 2020, ISSN: 2076-2607.
@article{microorganisms8081252,
title = {The Absence of C-5 DNA Methylation in Leishmania donovani Allows DNA Enrichment from Complex Samples},
author = {Bart Cuypers and Franck Dumetz and Pieter Meysman and Kris Laukens and G\'{e}raldine De Muylder and Jean-Claude Dujardin and Malgorzata Anna Domagalska},
url = {https://www.mdpi.com/2076-2607/8/8/1252},
doi = {10.3390/microorganisms8081252},
issn = {2076-2607},
year = {2020},
date = {2020-01-01},
journal = {Microorganisms},
volume = {8},
number = {8},
abstract = {Cytosine C5 methylation is an important epigenetic control mechanism in a wide array of eukaryotic organisms and generally carried out by proteins of the C-5 DNA methyltransferase family (DNMTs). In several protozoans, the status of this mechanism remains elusive, such as in Leishmania, the causative agent of the disease leishmaniasis in humans and a wide array of vertebrate animals. In this work, we showed that the Leishmania donovani genome contains a C-5 DNA methyltransferase (DNMT) from the DNMT6 subfamily, whose function is still unclear, and verified its expression at the RNA level. We created viable overexpressor and knock-out lines of this enzyme and characterized their genome-wide methylation patterns using whole-genome bisulfite sequencing, together with promastigote and amastigote control lines. Interestingly, despite the DNMT6 presence, we found that methylation levels were equal to or lower than 0.0003% at CpG sites, 0.0005% at CHG sites, and 0.0126% at CHH sites at the genomic scale. As none of the methylated sites were retained after manual verification, we conclude that there is no evidence for DNA methylation in this species. We demonstrated that this difference in DNA methylation between the parasite (no detectable DNA methylation) and the vertebrate host (DNA methylation) allowed enrichment of parasite vs. host DNA using methyl-CpG-binding domain columns, readily available in commercial kits. As such, we depleted methylated DNA from mixes of Leishmania promastigote and amastigote DNA with human DNA, resulting in average Leishmania:human enrichments from 62\× up to 263\×. These results open a promising avenue for unmethylated DNA enrichment as a pre-enrichment step before sequencing Leishmania clinical samples.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Uzureau, Sophie; Lecordier, Laurence; Uzureau, Pierrick; Hennig, Dorle; Graversen, Jonas H; Homblé, Fabrice; Mfutu, Pepe Ekulu; Arcolino], Fanny [Oliveira; Ramos, Ana Raquel; Rovere], Rita [La M; Luyten, Tomas; Vermeersch, Marjorie; Tebabi, Patricia; Dieu, Marc; Cuypers, Bart; Deborggraeve, Stijn; Rabant, Marion; Legendre, Christophe; Moestrup, Søren K; Levtchenko, Elena; Bultynck, Geert; Erneux, Christophe; Pérez-Morga, David; Pays, Etienne
APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin Journal Article
In: Cell Reports, vol. 30, no. 11, pp. 3821 - 3836.e13, 2020, ISSN: 2211-1247.
@article{UZUREAU20203821,
title = {APOL1 C-Terminal Variants May Trigger Kidney Disease through Interference with APOL3 Control of Actomyosin},
author = {Sophie Uzureau and Laurence Lecordier and Pierrick Uzureau and Dorle Hennig and Jonas H Graversen and Fabrice Hombl\'{e} and Pepe Ekulu Mfutu and Fanny [Oliveira Arcolino] and Ana Raquel Ramos and Rita [La M Rovere] and Tomas Luyten and Marjorie Vermeersch and Patricia Tebabi and Marc Dieu and Bart Cuypers and Stijn Deborggraeve and Marion Rabant and Christophe Legendre and S\oren K Moestrup and Elena Levtchenko and Geert Bultynck and Christophe Erneux and David P\'{e}rez-Morga and Etienne Pays},
url = {http://www.sciencedirect.com/science/article/pii/S2211124720302321},
doi = {https://doi.org/10.1016/j.celrep.2020.02.064},
issn = {2211-1247},
year = {2020},
date = {2020-01-01},
journal = {Cell Reports},
volume = {30},
number = {11},
pages = {3821 - 3836.e13},
abstract = {Summary
The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB). Both APOL1 and APOL3 can form K+ channels, but only APOL3 exhibits Ca2+-dependent binding of high affinity to neuronal calcium sensor-1 (NCS-1), promoting NCS-1-PI4KB interaction and stimulating PI4KB activity. Alteration of the APOL1 C-terminal helix triggers APOL1 unfolding and increased binding to APOL3, affecting APOL3-NCS-1 interaction. Since the podocytes of G1 and G2 patients exhibit an APOL1Δ or APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, with consecutive actomyosin reorganization of podocytes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The C-terminal variants G1 and G2 of apolipoprotein L1 (APOL1) confer human resistance to the sleeping sickness parasite Trypanosoma rhodesiense, but they also increase the risk of kidney disease. APOL1 and APOL3 are death-promoting proteins that are partially associated with the endoplasmic reticulum and Golgi membranes. We report that in podocytes, either APOL1 C-terminal helix truncation (APOL1Δ) or APOL3 deletion (APOL3KO) induces similar actomyosin reorganization linked to the inhibition of phosphatidylinositol-4-phosphate [PI(4)P] synthesis by the Golgi PI(4)-kinase IIIB (PI4KB). Both APOL1 and APOL3 can form K+ channels, but only APOL3 exhibits Ca2+-dependent binding of high affinity to neuronal calcium sensor-1 (NCS-1), promoting NCS-1-PI4KB interaction and stimulating PI4KB activity. Alteration of the APOL1 C-terminal helix triggers APOL1 unfolding and increased binding to APOL3, affecting APOL3-NCS-1 interaction. Since the podocytes of G1 and G2 patients exhibit an APOL1Δ or APOL3KO-like phenotype, APOL1 C-terminal variants may induce kidney disease by preventing APOL3 from activating PI4KB, with consecutive actomyosin reorganization of podocytes.
2018
Cuypers, Bart; Berg, Maya; Imamura, Hideo; Dumetz, Franck; Muylder], Géraldine [De; Domagalska, Malgorzata A; Rijal, Suman; Bhattarai, Narayan Raj; Maes, Ilse; Sanders, Mandy; Cotton, James A; Meysman, Pieter; Laukens, Kris; Dujardin, Jean-Claude
Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent Journal Article
In: Infection, Genetics and Evolution, vol. 62, pp. 170 - 178, 2018, ISSN: 1567-1348.
@article{CUYPERS2018170,
title = {Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent},
author = {Bart Cuypers and Maya Berg and Hideo Imamura and Franck Dumetz and G\'{e}raldine [De Muylder] and Malgorzata A Domagalska and Suman Rijal and Narayan Raj Bhattarai and Ilse Maes and Mandy Sanders and James A Cotton and Pieter Meysman and Kris Laukens and Jean-Claude Dujardin},
url = {http://www.sciencedirect.com/science/article/pii/S1567134818302004},
doi = {https://doi.org/10.1016/j.meegid.2018.04.021},
issn = {1567-1348},
year = {2018},
date = {2018-01-01},
journal = {Infection, Genetics and Evolution},
volume = {62},
pages = {170 - 178},
abstract = {Leishmania donovani is the responsible agent for visceral leishmaniasis (VL) in the Indian subcontinent (ISC). The disease is lethal without treatment and causes 0.2 to 0.4 million cases each year. Recently, reports of VL in Nepalese hilly districts have increased as well as VL cases caused by L. donovani from the ISC1 genetic group, a new and emerging genotype. In this study, we perform for the first time an integrated, untargeted genomics and metabolomics approach to characterize ISC1, in comparison with the Core Group (CG), main population that drove the most recent outbreak of VL in the ISC. We show that the ISC1 population is very different from the CG, both at genome and metabolome levels. The genomic differences include SNPs, CNV and small indels in genes coding for known virulence factors, immunogens and surface proteins. Both genomic and metabolic approaches highlighted dissimilarities related to membrane lipids, the nucleotide salvage pathway and the urea cycle in ISC1 versus CG. Many of these pathways and molecules are important for the interaction with the host/extracellular environment. Altogether, our data predict major functional differences in ISC1 versus CG parasites, including virulence. Therefore, particular attention is required to monitor the fate of this emerging ISC1 population in the ISC, especially in a post-VL elimination context.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cuypers, Bart
A systems biology approach for a comprehensive understanding of molecular adaptation in** Leishmania donovani PhD Thesis
University of Antwerp, 2018.
@phdthesis{cuypers2018systems,
title = {A systems biology approach for a comprehensive understanding of molecular adaptation in** Leishmania donovani},
author = {Bart Cuypers},
year = {2018},
date = {2018-01-01},
school = {University of Antwerp},
keywords = {},
pubstate = {published},
tppubtype = {phdthesis}
}
2017
Cuypers, Bart; den Broeck, Frederik Van; Reet, Nick Van; Meehan, Conor J; Cauchard, Julien; Wilkes, Jonathan M; Claes, Filip; Goddeeris, Bruno; Birhanu, Hadush; Dujardin, Jean-Claude; Laukens, Kris; Büscher, Philippe; Deborggraeve, Stijn
Genome-Wide SNP Analysis Reveals Distinct Origins of Trypanosoma evansi and Trypanosoma equiperdum Journal Article
In: Genome Biology and Evolution, vol. 9, no. 8, pp. 1990-1997, 2017, ISSN: 1759-6653.
@article{Cuypers2017b,
title = {Genome-Wide SNP Analysis Reveals Distinct Origins of Trypanosoma evansi and Trypanosoma equiperdum},
author = {Bart Cuypers and Frederik Van den Broeck and Nick Van Reet and Conor J Meehan and Julien Cauchard and Jonathan M Wilkes and Filip Claes and Bruno Goddeeris and Hadush Birhanu and Jean-Claude Dujardin and Kris Laukens and Philippe B\"{u}scher and Stijn Deborggraeve},
url = {https://doi.org/10.1093/gbe/evx102},
doi = {10.1093/gbe/evx102},
issn = {1759-6653},
year = {2017},
date = {2017-05-25},
journal = {Genome Biology and Evolution},
volume = {9},
number = {8},
pages = {1990-1997},
abstract = {Trypanosomes cause a variety of diseases in man and domestic animals in Africa, Latin America, and Asia. In the Trypanozoon subgenus, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense cause human African trypanosomiasis, whereas Trypanosoma brucei brucei, Trypanosoma evansi, and Trypanosoma equiperdum are responsible for nagana, surra, and dourine in domestic animals, respectively. The genetic relationships between T. evansi and T. equiperdum and other Trypanozoon species remain unclear because the majority of phylogenetic analyses has been based on only a few genes. In this study, we have conducted a phylogenetic analysis based on genome-wide SNP analysis comprising 56 genomes from the Trypanozoon subgenus. Our data reveal that T. equiperdum has emerged at least once in Eastern Africa and T. evansi at two independent occasions in Western Africa. The genomes within the T. equiperdum and T. evansi monophyletic clusters show extremely little variation, probably due to the clonal spread linked to the independence from tsetse flies for their transmission.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dumetz, F; Imamura, H; Sanders, M; Seblova, V; Myskova, J; Pescher, P; Vanaerschot, M; Meehan, C J; Cuypers, B; Muylder, G De; Späth, G F; Bussotti, G; Vermeesch, J R; Berriman, M; Cotton, J A; Volf, P; Dujardin, J C; Domagalska, M A
In: mBio, vol. 8, no. 3, 2017.
@article{Dumetze00599-17,
title = {Modulation of Aneuploidy in Leishmania donovani during Adaptation to Different In Vitro and In Vivo Environments and Its Impact on Gene Expression},
author = {F Dumetz and H Imamura and M Sanders and V Seblova and J Myskova and P Pescher and M Vanaerschot and C J Meehan and B Cuypers and G De Muylder and G F Sp\"{a}th and G Bussotti and J R Vermeesch and M Berriman and J A Cotton and P Volf and J C Dujardin and M A Domagalska},
editor = {Keith Gull},
url = {https://mbio.asm.org/content/8/3/e00599-17},
doi = {10.1128/mBio.00599-17},
year = {2017},
date = {2017-01-01},
journal = {mBio},
volume = {8},
number = {3},
publisher = {American Society for Microbiology},
abstract = {Aneuploidy is usually deleterious in multicellular organisms but appears to be tolerated and potentially beneficial in unicellular organisms, including pathogens. Leishmania, a major protozoan parasite, is emerging as a new model for aneuploidy, since in vitro-cultivated strains are highly aneuploid, with interstrain diversity and intrastrain mosaicism. The alternation of two life stages in different environments (extracellular promastigotes and intracellular amastigotes) offers a unique opportunity to study the impact of environment on aneuploidy and gene expression. We sequenced the whole genomes and transcriptomes of Leishmania donovani strains throughout their adaptation to in vivo conditions mimicking natural vertebrate and invertebrate host environments. The nucleotide sequences were almost unchanged within a strain, in contrast to highly variable aneuploidy. Although high in promastigotes in vitro, aneuploidy dropped significantly in hamster amastigotes, in a progressive and strain-specific manner, accompanied by the emergence of new polysomies. After a passage through a sand fly, smaller yet consistent karyotype changes were detected. Changes in chromosome copy numbers were correlated with the corresponding transcript levels, but additional aneuploidy-independent regulation of gene expression was observed. This affected stage-specific gene expression, downregulation of the entire chromosome 31, and upregulation of gene arrays on chromosomes 5 and 8. Aneuploidy changes in Leishmania are probably adaptive and exploited to modulate the dosage and expression of specific genes; they are well tolerated, but additional mechanisms may exist to regulate the transcript levels of other genes located on aneuploid chromosomes. Our model should allow studies of the impact of aneuploidy on molecular adaptations and cellular fitness.IMPORTANCE Aneuploidy is usually detrimental in multicellular organisms, but in several microorganisms, it can be tolerated and even beneficial. Leishmania\textemdasha protozoan parasite that kills more than 30,000 people each year\textemdashis emerging as a new model for aneuploidy studies, as unexpectedly high levels of aneuploidy are found in clinical isolates. Leishmania lacks classical regulation of transcription at initiation through promoters, so aneuploidy could represent a major adaptive strategy of this parasite to modulate gene dosage in response to stressful environments. For the first time, we document the dynamics of aneuploidy throughout the life cycle of the parasite, in vitro and in vivo. We show its adaptive impact on transcription and its interaction with regulation. Besides offering a new model for aneuploidy studies, we show that further genomic studies should be done directly in clinical samples without parasite isolation and that adequate methods should be developed for this.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2016
Imamura, Hideo; Downing, Tim; den Broeck, Frederik Van; Sanders, Mandy J; Rijal, Suman; Sundar, Shyam; Mannaert, An; Vanaerschot, Manu; Berg, Maya; Muylder, Géraldine De; Dumetz, Franck; Cuypers, Bart; Maes, Ilse; Domagalska, Malgorzata; Decuypere, Saskia; Rai, Keshav; Uranw, Surendra; Bhattarai, Narayan Raj; Khanal, Basudha; Prajapati, Vijay Kumar; Sharma, Smriti; Stark, Olivia; Schönian, Gabriele; Koning, Harry P De; Settimo, Luca; Vanhollebeke, Benoit; Roy, Syamal; Ostyn, Bart; Boelaert, Marleen; Maes, Louis; Berriman, Matthew; Dujardin, Jean-Claude; Cotton, James A
Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent Journal Article
In: eLife, vol. 5, pp. e12613, 2016, ISSN: 2050-084X.
@article{10.7554/eLife.12613,
title = {Evolutionary genomics of epidemic visceral leishmaniasis in the Indian subcontinent},
author = {Hideo Imamura and Tim Downing and Frederik Van den Broeck and Mandy J Sanders and Suman Rijal and Shyam Sundar and An Mannaert and Manu Vanaerschot and Maya Berg and G\'{e}raldine De Muylder and Franck Dumetz and Bart Cuypers and Ilse Maes and Malgorzata Domagalska and Saskia Decuypere and Keshav Rai and Surendra Uranw and Narayan Raj Bhattarai and Basudha Khanal and Vijay Kumar Prajapati and Smriti Sharma and Olivia Stark and Gabriele Sch\"{o}nian and Harry P De Koning and Luca Settimo and Benoit Vanhollebeke and Syamal Roy and Bart Ostyn and Marleen Boelaert and Louis Maes and Matthew Berriman and Jean-Claude Dujardin and James A Cotton},
editor = {Dominique Soldati-Favre},
url = {https://doi.org/10.7554/eLife.12613},
doi = {10.7554/eLife.12613},
issn = {2050-084X},
year = {2016},
date = {2016-03-01},
journal = {eLife},
volume = {5},
pages = {e12613},
publisher = {eLife Sciences Publications, Ltd},
abstract = {textitLeishmania donovani causes visceral leishmaniasis (VL), the second most deadly vector-borne parasitic disease. A recent epidemic in the Indian subcontinent (ISC) caused up to 80% of global VL and over 30,000 deaths per year. Resistance against antimonial drugs has probably been a contributing factor in the persistence of this epidemic. Here we use whole genome sequences from 204 clinical isolates to track the evolution and epidemiology of textitL. donovani from the ISC. We identify independent radiations that have emerged since a bottleneck coincident with 1960s DDT spraying campaigns. A genetically distinct population frequently resistant to antimonials has a two base-pair insertion in the aquaglyceroporin gene LdAQP1 that prevents the transport of trivalent antimonials. We find evidence of genetic exchange between ISC populations, and show that the mutation in LdAQP1 has spread by recombination. Our results reveal the complexity of textitL. donovani evolution in the ISC in response to drug treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mondelaers, Annelies; Sanchez-Cañete, Maria P; Hendrickx, Sarah; Eberhardt, Eline; Garcia-Hernandez, Raquel; Lachaud, Laurence; Cotton, James; Sanders, Mandy; Cuypers, Bart; Imamura, Hideo; Dujardin, Jean-Claude; Delputte, Peter; Cos, Paul; Caljon, Guy; Gamarro, Francisco; Castanys, Santiago; Maes, Louis
In: PLOS ONE, vol. 11, no. 4, pp. 1-15, 2016.
@article{10.1371/journal.pone.0154101,
title = {Genomic and Molecular Characterization of Miltefosine Resistance in Leishmania infantum Strains with Either Natural or Acquired Resistance through Experimental Selection of Intracellular Amastigotes},
author = {Annelies Mondelaers and Maria P Sanchez-Ca\~{n}ete and Sarah Hendrickx and Eline Eberhardt and Raquel Garcia-Hernandez and Laurence Lachaud and James Cotton and Mandy Sanders and Bart Cuypers and Hideo Imamura and Jean-Claude Dujardin and Peter Delputte and Paul Cos and Guy Caljon and Francisco Gamarro and Santiago Castanys and Louis Maes},
url = {https://doi.org/10.1371/journal.pone.0154101},
doi = {10.1371/journal.pone.0154101},
year = {2016},
date = {2016-01-01},
journal = {PLOS ONE},
volume = {11},
number = {4},
pages = {1-15},
publisher = {Public Library of Science},
abstract = {During the last decade miltefosine (MIL) has been used as first-line treatment for visceral leishmaniasis in endemic areas with antimonial resistance, but a decline in clinical effectiveness is now being reported. While only two MIL-resistant Leishmania infantum strains from HIV co-infected patients have been documented, phenotypic MIL-resistance for L. donovani has not yet been identified in the laboratory. Hence, a better understanding of the factors contributing to increased MIL-treatment failure is necessary. Given the paucity of defined MIL-resistant L. donovani clinical isolates, this study used an experimental amastigote-selected MIL-resistant L. infantum isolate (LEM3323). In-depth exploration of the MIL-resistant phenotype was performed by coupling genomic with phenotypic data to gain insight into gene function and the mutant phenotype. A naturally MIL-resistant L. infantum clinical isolate (LEM5159) was included to compare both datasets. Phenotypically, resistance was evaluated by determining intracellular amastigote susceptibility in vitro and actual MIL-uptake. Genomic analysis provided supportive evidence that the resistance selection model on intracellular amastigotes can be a good proxy for the in vivo field situation since both resistant strains showed mutations in the same inward transporter system responsible for the acquired MIL-resistant phenotype. In line with previous literature findings in promastigotes, our data confirm a defective import machinery through inactivation of the LiMT/LiRos3 protein complex as the main mechanism for MIL-resistance also in intracellular amastigotes. Whole genome sequencing analysis of LEM3323 revealed a 2 base pair deletion in the LiMT gene that led to the formation an early stop codon and a truncation of the LiMT protein. Interestingly, LEM5159 revealed mutations in both the LiMT and LiRos3 genes, resulting in an aberrant expression of the LiMT protein. To verify that these mutations were indeed accountable for the acquired resistance, transfection experiments were performed to re-establish MIL-susceptibility. In LEM3323, susceptibility was restored upon expression of a LiMT wild-type gene, whereas the MIL-susceptibility of LEM5159 could be reversed after expression of the LiRos3 wild-type gene. The aberrant expression profile of the LiMT protein could be restored upon rescue of the LiRos3 gene both in the LEM5159 clinical isolate and a ΔLiRos3 strain, showing that expression of LdMT is dependent on LdRos3 expression. The present findings clearly corroborate the pivotal role of the LiMT/LiRos3 complex in resistance towards MIL.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Cuypers, Bart; Lecordier, Laurence; Meehan, Conor J; den Broeck, Frederik Van; Imamura, Hideo; Büscher, Philippe; Dujardin, Jean-Claude; Laukens, Kris; Schnaufer, Achim; Dewar, Caroline; Lewis, Michael; Balmer, Oliver; Azurago, Thomas; Kyei-Faried, Sardick; Ohene, Sally-Ann; Duah, Boateng; Homiah, Prince; Mensah, Ebenezer Kofi; Anleah, Francis; Franco, Jose Ramon; Pays, Etienne; Deborggraeve, Stijn
Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection Journal Article
In: mBio, vol. 7, no. 2, 2016.
@article{Cuyperse02198-15,
title = {Apolipoprotein L1 Variant Associated with Increased Susceptibility to Trypanosome Infection},
author = {Bart Cuypers and Laurence Lecordier and Conor J Meehan and Frederik Van den Broeck and Hideo Imamura and Philippe B\"{u}scher and Jean-Claude Dujardin and Kris Laukens and Achim Schnaufer and Caroline Dewar and Michael Lewis and Oliver Balmer and Thomas Azurago and Sardick Kyei-Faried and Sally-Ann Ohene and Boateng Duah and Prince Homiah and Ebenezer Kofi Mensah and Francis Anleah and Jose Ramon Franco and Etienne Pays and Stijn Deborggraeve},
editor = {Michael P Barrett and John C Boothroyd},
url = {https://mbio.asm.org/content/7/2/e02198-15},
doi = {10.1128/mBio.02198-15},
year = {2016},
date = {2016-01-01},
journal = {mBio},
volume = {7},
number = {2},
publisher = {American Society for Microbiology},
abstract = {African trypanosomes, except Trypanosoma brucei gambiense and Trypanosoma~brucei~rhodesiense, which cause human African trypanosomiasis, are lysed by the human serum protein apolipoprotein L1 (ApoL1). These two subspecies can resist human ApoL1 because they express the serum resistance proteins T. b. gambiense glycoprotein (TgsGP) and serum resistance-associated protein (SRA), respectively. Whereas in T.~b.~rhodesiense, SRA is necessary and sufficient to inhibit ApoL1, in T.~b.~gambiense, TgsGP cannot protect against high ApoL1 uptake, so different additional mechanisms contribute to limit this uptake. Here we report a complex interplay between trypanosomes and an ApoL1 variant, revealing important insights into innate human immunity against these parasites. Using whole-genome sequencing, we characterized an atypical T.~b.~gambiense infection in a patient in Ghana. We show that the infecting trypanosome has diverged from the classical T.~b.~gambiense strains and lacks the TgsGP defense mechanism against human serum. By sequencing the ApoL1 gene of the patient and subsequent in vitro mutagenesis experiments, we demonstrate that a homozygous missense substitution (N264K) in the membrane-addressing domain of this ApoL1 variant knocks down the trypanolytic activity, allowing the trypanosome to avoid ApoL1-mediated immunity.IMPORTANCE Most African trypanosomes are lysed by the ApoL1 protein in human serum. Only the subspecies Trypanosoma b. gambiense and T.~b.~rhodesiense can resist lysis by ApoL1 because they express specific serum resistance proteins. We here report a complex interplay between trypanosomes and an ApoL1 variant characterized by a homozygous missense substitution (N264K) in the domain that we hypothesize interacts with the endolysosomal membranes of trypanosomes. The N264K substitution knocks down the lytic activity of ApoL1 against T.~b.~gambiense strains lacking the TgsGP defense mechanism and against T.~b.~rhodesiense if N264K is accompanied by additional substitutions in the SRA-interacting domain. Our data suggest that populations with high frequencies of the homozygous N264K ApoL1 variant may be at increased risk of contracting human African trypanosomiasis.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}