Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1

PLoS Negl Trop Dis. 2015 Feb 25;9(2):e0003500. doi: 10.1371/journal.pntd.0003500. eCollection 2015 Feb.

Abstract

Leishmania is a digenetic protozoan parasite causing leishmaniasis in humans. The different clinical forms of leishmaniasis are caused by more than twenty species of Leishmania that are transmitted by nearly thirty species of phlebotomine sand flies. Pentavalent antimonials (such as Pentostam or Glucantime) are the first line drugs for treating leishmaniasis. Recent studies suggest that pentavalent antimony (Sb(V)) acts as a pro-drug, which is converted to the more active trivalent form (Sb(III)). However, sensitivity to trivalent antimony varies among different Leishmania species. In general, Leishmania species causing cutaneous leishmaniasis (CL) are more sensitive to Sb(III) than the species responsible for visceral leishmaniasis (VL). Leishmania aquaglyceroporin (AQP1) facilitates the adventitious passage of antimonite down a concentration gradient. In this study, we show that Leishmania species causing CL accumulate more antimonite, and therefore exhibit higher sensitivity to antimonials, than the species responsible for VL. This species-specific differential sensitivity to antimonite is directly proportional to the expression levels of AQP1 mRNA. We show that the stability of AQP1 mRNA in different Leishmania species is regulated by their respective 3'-untranslated regions. The differential regulation of AQP1 mRNA explains the distinct antimonial sensitivity of each species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • Antimony / chemistry
  • Antimony / metabolism
  • Antimony Sodium Gluconate / therapeutic use
  • Antiprotozoal Agents / therapeutic use*
  • Aquaglyceroporins / metabolism
  • Aquaporin 1 / genetics*
  • Cell Movement / genetics
  • Drug Resistance / genetics*
  • Gene Expression Regulation / genetics*
  • Humans
  • Leishmania / classification
  • Leishmania / drug effects
  • Leishmania / genetics*
  • Leishmaniasis, Cutaneous / drug therapy
  • Leishmaniasis, Cutaneous / parasitology
  • Leishmaniasis, Visceral / drug therapy
  • Leishmaniasis, Visceral / parasitology
  • Meglumine / therapeutic use
  • Meglumine Antimoniate
  • Organometallic Compounds / therapeutic use
  • RNA, Messenger / genetics
  • RNA, Protozoan / genetics

Substances

  • 3' Untranslated Regions
  • Antiprotozoal Agents
  • Aquaglyceroporins
  • Organometallic Compounds
  • RNA, Messenger
  • RNA, Protozoan
  • Aquaporin 1
  • antimonite
  • Meglumine
  • Meglumine Antimoniate
  • Antimony
  • Antimony Sodium Gluconate

Grants and funding

The study was funded by a Florida International University Herbert Wertheim College of Medicine Start-up fund to RM and a Florida International University Herbert Wertheim College of Medicine pilot fund to GM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.