HLA-DRB1 alleles associated with lower leishmaniasis susceptibility share common amino acid polymorphisms and epitope binding repertoires

Nicky de Vrij, Pieter Meysman, Sofie Gielis, Wim Adriaensen, Kris Laukens, Bart Cuypers

Research output: Contribution to journalA1: Web of Science-article

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.

Original languageEnglish
Article number270
JournalVaccines
Volume9
Issue number3
Number of pages17
ISSN2076-393X
DOIs
Publication statusPublished - 2021

Keywords

  • Leishmania
  • immunoinformatics
  • antigen presentation
  • HLA association
  • leishmaniasis
  • vaccine candidates
  • immunogenetics
  • human leukocyte antigen

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