Unveiling drug-tolerant and persister-like cells in Leishmania braziliensis lines derived from patients with cutaneous leishmaniasis

Marlene Jara, Jorge Arevalo, Alejandro Llanos-Cuentas, Frederik Van den Broeck, Malgorzata Anna Domagalska, Jean-Claude Dujardin

Research output: Contribution to journalA1: Web of Science-articlepeer-review

16 Downloads (Pure)

Abstract

INTRODUCTION: Resistance against anti-Leishmania drugs (DR) has been studied for years, giving important insights into long-term adaptations of these parasites to drugs, through genetic modifications. However, microorganisms can also survive lethal drug exposure by entering into temporary quiescence, a phenomenon called drug tolerance (DT), which is rather unexplored in Leishmania.

METHODS: We studied a panel of nine Leishmania braziliensis strains highly susceptible to potassium antimonyl tartrate (PAT), exposed promastigotes to lethal PAT pressure, and compared several cellular and molecular parameters distinguishing DT from DR.

RESULTS AND DISCUSSION: We demonstrated in vitro that a variable proportion of cells remained viable, showing all the criteria of DT and not of DR: i) signatures of quiescence, under drug pressure: reduced proliferation and significant decrease of rDNA transcription; ii) reversibility of the phenotype: return to low IC50 after removal of drug pressure; and iii) absence of significant genetic differences between exposed and unexposed lineages of each strain and absence of reported markers of DR. We found different levels of quiescence and DT among the different L. braziliensis strains. We provide here a new in-vitro model of drug-induced quiescence and DT in Leishmania. Research should be extended in vivo, but the current model could be further exploited to support R&D, for instance, to guide the screening of compounds to overcome the quiescence resilience of the parasite, thereby improving the therapy of leishmaniasis.

Original languageEnglish
Article number1253033
JournalFrontiers in Cellular and Infection Microbiology
Volume13
Number of pages11
ISSN2235-2988
DOIs
Publication statusPublished - 2023

Keywords

  • Humans
  • Leishmania braziliensis/genetics
  • Leishmaniasis, Cutaneous/drug therapy
  • Leishmania

Fingerprint

Dive into the research topics of 'Unveiling drug-tolerant and persister-like cells in Leishmania braziliensis lines derived from patients with cutaneous leishmaniasis'. Together they form a unique fingerprint.

Cite this