title: Species-specific antimonial sensitivity in Leishmania is driven by post-transcriptional regulation of AQP1.
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.
authors.affiliation: Department of Cellular Biology and Pharmacology, Florida International University, Herbert Wertheim College of Medicine, Florida, United States of America.
authors.forename: Goutam
authors.initials: G
authors.lastname: Mandal
authors.affiliation: Department of Cellular Biology and Pharmacology, Florida International University, Herbert Wertheim College of Medicine, Florida, United States of America.
authors.forename: Srotoswati
authors.initials: S
authors.lastname: Mandal
authors.affiliation: Department of Cellular Biology and Pharmacology, Florida International University, Herbert Wertheim College of Medicine, Florida, United States of America.
authors.forename: Mansi
authors.initials: M
authors.lastname: Sharma
authors.affiliation: CHU de Quebec Research Center and Department of Microbiology-Infectious Disease and Immunology, University Laval, Quebec, Canada.
authors.forename: Karen Santos
authors.initials: KS
authors.lastname: Charret
authors.affiliation: CHU de Quebec Research Center and Department of Microbiology-Infectious Disease and Immunology, University Laval, Quebec, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Papadopoulou
authors.affiliation: Department of Cellular Biology and Pharmacology, Florida International University, Herbert Wertheim College of Medicine, Florida, United States of America.
authors.forename: Hiranmoy
authors.initials: H
authors.lastname: Bhattacharjee
authors.affiliation: Department of Cellular Biology and Pharmacology, Florida International University, Herbert Wertheim College of Medicine, Florida, United States of America.
authors.forename: Rita
authors.initials: R
authors.lastname: Mukhopadhyay
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics*; D000965:Antimony / Q000737:chemistry / Q000378:metabolism; D000967:Antimony Sodium Gluconate / Q000627:therapeutic use; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D051397:Aquaglyceroporins / Q000378:metabolism; D051398:Aquaporin 1 / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007891:Leishmania / Q000145:classification / Q000187:drug effects / Q000235:genetics*; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy / Q000469:parasitology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D008536:Meglumine / Q000627:therapeutic use; D000077485:Meglumine Antimoniate; D009942:Organometallic Compounds / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics; D016053:RNA, Protozoan / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D000981:Antiprotozoal Agents; D051397:Aquaglyceroporins; D009942:Organometallic Compounds; D012333:RNA, Messenger; D016053:RNA, Protozoan; D051398:Aquaporin 1; C061374:antimonite; D008536:Meglumine; D000077485:Meglumine Antimoniate; D000965:Antimony; D000967:Antimony Sodium Gluconate