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Citations: 1319
H-Index: 18
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2021
de Vrij, Nicky; Meysman, Pieter; Gielis, Sofie; Adriaensen, Wim; Laukens, Kris; Cuypers, Bart
HLA-DRB1 Alleles Associated with Lower Leishmaniasis Susceptibility Share Common Amino Acid Polymorphisms and Epitope Binding Repertoires Journal Article
In: Vaccines, vol. 9, no. 3, 2021, ISSN: 2076-393X.
@article{vaccines9030270,
title = {HLA-DRB1 Alleles Associated with Lower Leishmaniasis Susceptibility Share Common Amino Acid Polymorphisms and Epitope Binding Repertoires},
author = {Nicky de Vrij and Pieter Meysman and Sofie Gielis and Wim Adriaensen and Kris Laukens and Bart Cuypers},
url = {https://www.mdpi.com/2076-393X/9/3/270},
doi = {10.3390/vaccines9030270},
issn = {2076-393X},
year = {2021},
date = {2021-01-01},
journal = {Vaccines},
volume = {9},
number = {3},
abstract = {Susceptibility for leishmaniasis is largely dependent on host genetic and immune factors. Despite the previously described association of human leukocyte antigen (HLA) gene cluster variants as genetic susceptibility factors for leishmaniasis, little is known regarding the mechanisms that underpin these associations. To better understand this underlying functionality, we first collected all known leishmaniasis-associated HLA variants in a thorough literature review. Next, we aligned and compared the protection- and risk-associated HLA-DRB1 allele sequences. This identified several amino acid polymorphisms that distinguish protection- from risk-associated HLA-DRB1 alleles. Subsequently, T cell epitope binding predictions were carried out across these alleles to map the impact of these polymorphisms on the epitope binding repertoires. For these predictions, we used epitopes derived from entire proteomes of multiple Leishmania species. Epitopes binding to protection-associated HLA-DRB1 alleles shared common binding core motifs, mapping to the identified HLA-DRB1 amino acid polymorphisms. These results strongly suggest that HLA polymorphism, resulting in differential antigen presentation, affects the association between HLA and leishmaniasis disease development. Finally, we established a valuable open-access resource of putative epitopes. A set of 14 HLA-unrestricted strong-binding epitopes, conserved across species, was prioritized for further epitope discovery in the search for novel subunit-based vaccines.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
2015
Berg, Maya; Garc'ia-Hernández, Raquel; Cuypers, Bart; Vanaerschot, Manu; Manzano, José I; Poveda, José A; Ferragut, José A; Castanys, Santiago; Dujardin, Jean-Claude; Gamarro, Francisco
Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations Journal Article
In: Antimicrobial Agents and Chemotherapy, vol. 59, no. 4, pp. 2242–2255, 2015, ISSN: 0066-4804.
@article{Berg2242,
title = {Experimental Resistance to Drug Combinations in Leishmania donovani: Metabolic and Phenotypic Adaptations},
author = {Maya Berg and Raquel Garc{'i}a-Hern\'{a}ndez and Bart Cuypers and Manu Vanaerschot and Jos\'{e} I Manzano and Jos\'{e} A Poveda and Jos\'{e} A Ferragut and Santiago Castanys and Jean-Claude Dujardin and Francisco Gamarro},
url = {https://aac.asm.org/content/59/4/2242},
doi = {10.1128/AAC.04231-14},
issn = {0066-4804},
year = {2015},
date = {2015-01-01},
journal = {Antimicrobial Agents and Chemotherapy},
volume = {59},
number = {4},
pages = {2242--2255},
publisher = {American Society for Microbiology Journals},
abstract = {Together with vector control, chemotherapy is an essential tool for the control of visceral leishmaniasis (VL), but its efficacy is jeopardized by growing resistance and treatment failure against first-line drugs. To delay the emergence of resistance, the use of drug combinations of existing antileishmanial agents has been tested systematically in clinical trials for the treatment of visceral leishmaniasis (VL). In vitro, Leishmania donovani promastigotes are able to develop experimental resistance to several combinations of different antileishmanial drugs after 10 weeks of drug pressure. Using an untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics approach, we identified metabolic changes in lines that were experimentally resistant to drug combinations and their respective single-resistant lines. This highlighted both collective metabolic changes (found in all combination therapy-resistant [CTR] lines) and specific ones (found in certain CTR lines). We demonstrated that single-resistant and CTR parasite cell lines show distinct metabolic adaptations, which all converge on the same defensive mechanisms that were experimentally validated: protection against drug-induced and external oxidative stress and changes in membrane fluidity. The membrane fluidity changes were accompanied by changes in drug uptake only in the lines that were resistant against drug combinations with antimonials, and surprisingly, drug accumulation was higher in these lines. Together, these results highlight the importance and the central role of protection against oxidative stress in the different resistant lines. Ultimately, these phenotypic changes might interfere with the mode of action of all drugs that are currently used for the treatment of VL and should be taken into account in drug development.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}